Scholars@Duke
Vandana Shashi

Vandana Shashi

Professor of Pediatrics
Pediatrics, Medical Genetics
vandana.shashi@duke.edu
Box 3528 Med Ctr, Durham, NC 27710
2080 GSRB, Durham, NC 27710

Selected Publications

Enriched phenotypes in rare variant carriers suggest pathogenic mechanisms in rare disease patients

Journal Article Biodata Mining · December 1, 2025 Background: The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the under ... Full text Cite

The book is just being written: The enduring journey of parents of children with emerging- ultrarare disorders.

Journal Article J Genet Couns · February 2025 Ultra rare disorders are being diagnosed at an unprecedented rate, due to genomic sequencing. These diagnoses are often a new gene association, for which little is known, and few share the diagnosis. For these diagnoses, we use the term emerging-ultrarare ... Full text Link to item Cite

Dominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.

Journal Article Genet Med · September 2024 PURPOSE: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestati ... Full text Link to item Cite

MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

Journal Article Am J Hum Genet · July 11, 2024 Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotem ... Full text Link to item Cite

A second hotspot for pathogenic exon-skipping variants in CDC45.

Journal Article Eur J Hum Genet · July 2024 Biallelic pathogenic variants in CDC45 are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and absent/hypoplastic patellae. Identified variants act through a hypomorphic loss of function mechani ... Full text Link to item Cite

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

Journal Article Cell Mol Life Sci · March 28, 2024 N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a ... Full text Link to item Cite

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Journal Article medRxiv · January 31, 2024 Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying ... Full text Link to item Cite

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Journal Article J Clin Invest · January 2, 2024 Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF1 ... Full text Link to item Cite

The best of both worlds: Blending cutting-edge research with clinical processes for a productive exome clinic.

Journal Article Clin Genet · January 2024 Genomic medicine has been transformed by next-generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid pro ... Full text Link to item Cite

Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors.

Journal Article J Genet Couns · October 2023 Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation wo ... Full text Open Access Link to item Cite

Parental perspectives of episodic irritability in an ultra-rare genetic disorder associated with NACC1.

Journal Article Orphanet J Rare Dis · September 4, 2023 BACKGROUND: A recurrent de novo variant (c.892C>T) in NACC1 causes a neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM). An unusual and consistently reported feature is episodic extreme irritab ... Full text Link to item Cite

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

Journal Article Genet Med · September 2023 PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, ... Full text Link to item Cite

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Journal Article NPJ Genom Med · July 18, 2023 Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of ... Full text Link to item Cite

Bi-allelic variants in INTS11 are associated with a complex neurological disorder.

Journal Article Am J Hum Genet · May 4, 2023 The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator ... Full text Link to item Cite

A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network.

Journal Article Genet Med · April 2023 PURPOSE: Next-generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultrarare conditions. However, diagnosis rates differ between analytical pipelines. In the National Institutes of Health-Undiagnosed Diseases Network (UDN) study, ... Full text Link to item Cite

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Journal Article Am J Hum Genet · March 2, 2023 Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKK ... Full text Link to item Cite

Exome/Genome Sequencing in Undiagnosed Syndromes.

Journal Article Annu Rev Med · January 27, 2023 Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, h ... Full text Link to item Cite

Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome.

Journal Article Brain · October 21, 2022 The endocannabinoid system is a highly conserved and ubiquitous signalling pathway with broad-ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from ... Full text Link to item Cite

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Journal Article Am J Hum Genet · October 6, 2022 Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals ... Full text Link to item Cite

The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.

Journal Article Hum Mol Genet · August 25, 2022 DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with pro ... Full text Open Access Link to item Cite

Expanding the phenotypic spectrum of ARCN1-related syndrome.

Journal Article Genet Med · June 2022 PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinica ... Full text Link to item Cite

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Journal Article Am J Hum Genet · March 3, 2022 Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, m ... Full text Link to item Cite

Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.

Journal Article Am J Hum Genet · February 3, 2022 Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predi ... Full text Link to item Cite

Clinical application of a scale to assess genomic healthcare empowerment (GEmS): Process and illustrative case examples.

Journal Article J Genet Couns · February 2022 The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empo ... Full text Link to item Cite

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

Journal Article Genet Med · October 2021 PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several ... Full text Link to item Cite

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Journal Article Mol Psychiatry · August 2021 Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in additi ... Full text Link to item Cite

Next-generation sequencing for constitutional variants in the clinical laboratory, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Journal Article Genet Med · August 2021 Next-generation sequencing (NGS) technologies are now established in clinical laboratories as a primary testing modality in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude. It is now cost- ... Full text Link to item Cite

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.

Journal Article Am J Med Genet A · August 2021 Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease associatio ... Full text Link to item Cite

De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder.

Journal Article Am J Med Genet A · August 2021 TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the ... Full text Link to item Cite

Detection of a mosaic CDKL5 deletion and inversion by optical genome mapping ends an exhaustive diagnostic odyssey.

Journal Article Mol Genet Genomic Med · July 2021 BACKGROUND: Currently available structural variant (SV) detection methods do not span the complete spectrum of disease-causing SVs. Optical genome mapping (OGM), an emerging technology with the potential to resolve diagnostic dilemmas, was performed to inv ... Full text Link to item Cite

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy.

Journal Article Hum Genet · July 2021 Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of ... Full text Link to item Cite

Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features.

Journal Article Hum Mol Genet · June 26, 2021 The Polycomb group (PcG) gene RNF2 (RING2) encodes a catalytic subunit of the Polycomb repressive complex 1 (PRC1), an evolutionarily conserved machinery that post-translationally modifies chromatin to maintain epigenetic transcriptional repressive states ... Full text Link to item Cite

Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease.

Journal Article Hum Mutat · June 2021 KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate transfer RNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorin ... Full text Link to item Cite

A resource of lipidomics and metabolomics data from individuals with undiagnosed diseases.

Journal Article Sci Data · April 21, 2021 Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases ... Full text Link to item Cite

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Conference Genet Med · April 2021 PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. METHODS: Individua ... Full text Link to item Cite

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.

Journal Article Genet Med · April 2021 PURPOSE: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, fun ... Full text Link to item Cite

Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations.

Journal Article Epilepsy Behav · March 2021 BACKGROUND: ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments. AIM: We aimed to describe th ... Full text Open Access Link to item Cite

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Journal Article Am J Hum Genet · February 4, 2021 Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while t ... Full text Link to item Cite

A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.

Journal Article Eur J Hum Genet · February 2021 Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition i ... Full text Link to item Cite

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science.

Journal Article Genet Med · February 2021 PURPOSE: The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing t ... Full text Link to item Cite

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

Journal Article Genet Med · February 2021 PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by character ... Full text Link to item Cite

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.

Journal Article Genet Med · February 2021 PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 ... Full text Link to item Cite

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

Journal Article Nat Med · December 2020 The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-th ... Full text Link to item Cite

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Journal Article Molecular Genetics and Genomic Medicine · December 1, 2020 Background: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals repres ... Full text Cite

Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network.

Journal Article Mol Genet Genomic Med · October 2020 BACKGROUND: Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resou ... Full text Link to item Cite

D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.

Journal Article Neurol Genet · October 2020 OBJECTIVE: To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and ne ... Full text Open Access Link to item Cite

A pathogenic variant in the SETBP1 hotspot results in a forme-fruste Schinzel-Giedion syndrome.

Journal Article Am J Med Genet A · August 2020 Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, wit ... Full text Link to item Cite

Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses.

Journal Article Genet Med · July 2020 PURPOSE: Guidelines by professional organizations for assessing variant pathogenicity include the recommendation to utilize biologically relevant transcripts; however, there is variability in transcript selection by laboratories. METHODS: We describe three ... Full text Link to item Cite

Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome.

Journal Article Am J Med Genet A · May 2020 Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, l ... Full text Link to item Cite

PHENOTYPIC EXPANSION OF KMT2D-ASSOCIATED DISORDER: BEYOND KABUKI SYNDROME

Conference AMERICAN JOURNAL OF MEDICAL GENETICS PART A · April 1, 2020 Link to item Cite

Epileptic encephalopathy with features of rapid-onset dystonia Parkinsonism and alternating hemiplegia of childhood: a novel combination phenotype associated with ATP1A3 mutation.

Journal Article Epileptic Disord · February 1, 2020 Mutations in ATP1A3 have been found to cause rapid-onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four-year, nine-month-old boy with episodes of frequent and recurrent status epil ... Full text Link to item Cite

Predicting Autoimmunity Development in 22q11.2DS

Conference JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY · February 1, 2020 Link to item Cite

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Journal Article Biol Psychiatry · January 15, 2020 BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or ... Full text Link to item Cite

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

Journal Article J Clin Invest · January 2, 2020 Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mito ... Full text Link to item Cite

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

Journal Article Am J Hum Genet · January 2, 2020 The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of ... Full text Link to item Cite

The genome empowerment scale: An assessment of parental empowerment in families with undiagnosed disease.

Journal Article Clin Genet · December 2019 While genomic sequencing (ES/GS) has the potential to diagnose children with difficult to diagnose phenotypes, the goal should be not only a diagnosis, but also to empower parents to seek next steps for their children and to emotionally manage the outcome, ... Full text Link to item Cite

Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing.

Journal Article J Genet Couns · December 2019 BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yi ... Full text Link to item Cite

Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins.

Journal Article Hum Mol Genet · November 15, 2019 The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of p ... Full text Link to item Cite

Genomics in medicine: a novel elective rotation for internal medicine residents.

Journal Article Postgrad Med J · October 2019 It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to ... Full text Link to item Cite

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

Journal Article Am J Hum Genet · September 5, 2019 The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping de ... Full text Link to item Cite

Autism and developmental disability caused by KCNQ3 gain-of-function variants.

Journal Article Ann Neurol · August 2019 OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated ph ... Full text Link to item Cite

Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis.

Journal Article Hum Mutat · August 2019 Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families ... Full text Link to item Cite

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia.

Journal Article Am J Hum Genet · August 1, 2019 The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An i ... Full text Link to item Cite

ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis.

Journal Article Genetics in medicine : official journal of the American College of Medical Genetics · July 2019 PurposeDiagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to ... Full text Cite

Reported environmental exposures are inversely associated with obtaining a genetic diagnosis in the Undiagnosed Diseases Network.

Journal Article Am J Med Genet A · June 2019 The Undiagnosed Diseases Network (UDN) aims to achieve a unifying etiologic diagnosis for patients with mysterious conditions. Although the UDN has focused on the identification of genetic determinants, environmental etiologies may be causative or modifyin ... Full text Link to item Cite

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice-site and Charcot-Marie-Tooth phenotype with early onset symptoms.

Journal Article Mol Genet Genomic Med · June 2019 BACKGROUND: Rare variants (RV) in immunoglobulin mu-binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot-Marie-Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associat ... Full text Link to item Cite

Kilquist syndrome: A novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2.

Journal Article Hum Mutat · May 2019 Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss ... Full text Link to item Cite

A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing.

Journal Article J Genet Couns · April 2019 There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-dat ... Full text Link to item Cite

Hypogyrification and its association with cognitive impairment in children with 22q11.2 deletion Syndrome: A preliminary report.

Journal Article Psychiatry Res Neuroimaging · March 30, 2019 22q11.2 Deletion Syndrome (22qDS) is a neurogenetic disorder resulting in cognitive deficits and hypogyrification, but relationships between these processes have not been established. 22qDS youth and healthy controls (HC) were administered a battery of cog ... Full text Link to item Cite

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

Journal Article Am J Hum Genet · March 7, 2019 SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa ... Full text Link to item Cite

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Journal Article Am J Hum Genet · March 7, 2019 Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recr ... Full text Link to item Cite

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.

Journal Article Epilepsia · March 2019 OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potenti ... Full text Link to item Cite

Attention deficit hyperactivity disorder symptoms as antecedents of later psychotic outcomes in 22q11.2 deletion syndrome.

Journal Article Schizophr Res · February 2019 Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attentio ... Full text Link to item Cite

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Journal Article Am J Hum Genet · January 3, 2019 SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of t ... Full text Link to item Cite

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.

Journal Article Genet Med · January 2019 PURPOSE: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagno ... Full text Link to item Cite

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

Journal Article EMBO J · December 3, 2018 A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell dege ... Full text Link to item Cite

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

Journal Article N Engl J Med · November 29, 2018 BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologi ... Full text Link to item Cite

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

Journal Article Mol Psychiatry · November 2018 Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identifie ... Full text Open Access Link to item Cite

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Journal Article Cold Spring Harb Mol Case Stud · October 2018 Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little i ... Full text Link to item Cite

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

Journal Article Am J Med Genet A · October 2018 The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, ... Full text Link to item Cite

IRF2BPL Is Associated with Neurological Phenotypes.

Journal Article Am J Hum Genet · September 6, 2018 Full text Link to item Cite

Characteristics of undiagnosed diseases network applicants: implications for referring providers.

Journal Article BMC Health Serv Res · August 22, 2018 BACKGROUND: The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; ho ... Full text Link to item Cite

IRF2BPL Is Associated with Neurological Phenotypes.

Journal Article Am J Hum Genet · August 2, 2018 Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Her ... Full text Link to item Cite

Psychosocial Profiles of Parents of Children with Undiagnosed Diseases: Managing Well or Just Managing?

Journal Article J Genet Couns · August 2018 Little is known about the psychosocial profiles of parents who have a child with an undiagnosed chronic illness. The National Institutes of Health Undiagnosed Diseases Network (UDN) evaluates individuals with intractable medical findings, with the objectiv ... Full text Link to item Cite

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

Journal Article Hum Mol Genet · July 15, 2018 The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. ... Full text Link to item Cite

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

Journal Article Genet Med · April 2018 PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted sin ... Full text Open Access Link to item Cite

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder.

Journal Article Am J Hum Genet · March 1, 2018 ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each ... Full text Link to item Cite

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.

Journal Article Am J Hum Genet · October 5, 2017 Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common g ... Full text Link to item Cite

Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study.

Journal Article Schizophr Bull · September 1, 2017 Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a full-blown psychotic episode is usually preceded by subthreshold symptoms. In the current s ... Full text Link to item Cite

Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research.

Journal Article Genetics · September 2017 Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, a ... Full text Link to item Cite

MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome.

Journal Article Am J Hum Genet · June 1, 2017 One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth ... Full text Link to item Cite

A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network.

Journal Article Orphanet J Rare Dis · April 17, 2017 BACKGROUND: Patients' stories of their illnesses help bridge the divide between patients and providers, facilitating more humane medical care. Illness narratives have been classified into three types: restitution (expectation of recovery), chaos (suffering ... Full text Link to item Cite

No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients.

Journal Article Transl Psychiatry · February 21, 2017 The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25-30% of cases suffering from psychotic disorder ... Full text Link to item Cite

A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.

Journal Article Am J Hum Genet · January 5, 2017 Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that lo ... Full text Link to item Cite

Frontal Hypoactivation During a Working Memory Task in Children With 22q11 Deletion Syndrome.

Journal Article J Child Neurol · January 2017 Impairments in executive function, such as working memory, are almost universal in children with chromosome 22q11.2 deletion syndrome. Delineating the neural underpinnings of these functions would enhance understanding of these impairments. In this study, ... Full text Link to item Cite

Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant.

Journal Article Epilepsia · January 2017 Variants in KCNQ2 encoding for Kv 7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few incr ... Full text Link to item Cite

De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.

Journal Article Am J Hum Genet · October 6, 2016 The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 ... Full text Link to item Cite

Not the End of the Odyssey: Parental Perceptions of Whole Exome Sequencing (WES) in Pediatric Undiagnosed Disorders.

Journal Article J Genet Couns · October 2016 Due to the lack of empirical information on parental perceptions of primary results of whole exome sequencing (WES), we conducted a retrospective semi-structured interview with 19 parents of children who had undergone WES. Perceptions explored during the i ... Full text Link to item Cite

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Journal Article Am J Hum Genet · September 1, 2016 The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed anal ... Full text Link to item Cite

Epilepsy in KCNH1-related syndromes.

Journal Article Epileptic Disord · June 1, 2016 KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic fac ... Full text Link to item Cite

Practical considerations in the clinical application of whole-exome sequencing.

Journal Article Clin Genet · February 2016 Despite the exciting advent of whole-exome sequencing (WES) in medical genetics practices, the optimal interpretation of results requires further actions such as reconsidering clinical information and obtaining further laboratory testing. There are no publ ... Full text Link to item Cite

Communication of Psychiatric Risk in 22q11.2 Deletion Syndrome: A Pilot Project.

Journal Article J Genet Couns · February 2016 Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic couns ... Full text Link to item Cite

Quinidine in the treatment of KCNT1-positive epilepsies.

Journal Article Ann Neurol · December 2015 We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with ... Full text Link to item Cite

The RBMX gene as a candidate for the Shashi X-linked intellectual disability syndrome.

Journal Article Clin Genet · October 2015 A novel X-linked intellectual disability (XLID) syndrome with moderate intellectual disability and distinguishing craniofacial dysmorphisms had been previously mapped to the Xq26-q27 interval. On whole exome sequencing in the large family originally report ... Full text Link to item Cite

Parental Communication and Experiences and Knowledge of Adolescent Siblings of Children with 22q11.2 Deletion Syndrome.

Journal Article J Genet Couns · October 2015 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. There have been few studies assessing the impact of this condition on the family and no previous studies conducted on unaffected siblings of children with 22q11DS. The goal of ... Full text Link to item Cite

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.

Journal Article Genet Med · October 2015 PURPOSE: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. ... Full text Link to item Cite

Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention.

Journal Article J Intellect Disabil Res · October 2015 BACKGROUND: Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatr ... Full text Link to item Cite

Data sharing in the undiagnosed diseases network.

Journal Article Hum Mutat · October 2015 The Undiagnosed Diseases Network (UDN) builds on the successes of the Undiagnosed Diseases Program at the National Institutes of Health (NIH UDP). Through support from the NIH Common Fund, a coordinating center, six additional clinical sites, and two seque ... Full text Link to item Cite

Exome sequencing results in successful riboflavin treatment of a rapidly progressive neurological condition.

Journal Article Cold Spring Harb Mol Case Stud · October 2015 Genetically targeted therapies for rare Mendelian conditions are improving patient outcomes. Here, we present the case of a 20-mo-old female suffering from a rapidly progressing neurological disorder. Although diagnosed initially with a possible autoimmune ... Full text Link to item Cite

Sustained therapeutic response to riboflavin in a child with a progressive neurological condition, diagnosed by whole-exome sequencing.

Journal Article Cold Spring Harb Mol Case Stud · October 2015 One of the most promising outcomes of whole-exome sequencing (WES) is the alteration of medical management following an accurate diagnosis in patients with previously unresolved disorders. Although case reports of targeted therapies resulting from WES have ... Full text Link to item Cite

A tale worth telling: the impact of the diagnosis experience on disclosure of genetic disorders.

Journal Article J Intellect Disabil Res · May 2015 BACKGROUND: Research suggests children with genetic disorders exhibit greater coping skills when they are aware of their condition and its heritability. While the experiences parents have at diagnosis may influence their decision to disclose the diagnosis ... Full text Link to item Cite

Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome.

Journal Article JAMA Psychiatry · April 2015 IMPORTANCE: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a ... Full text Link to item Cite

De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

Journal Article Am J Hum Genet · March 5, 2015 Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a ... Full text Link to item Cite

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

Journal Article Genet Med · October 2014 PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype as ... Full text Open Access Link to item Cite

Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.

Journal Article Am J Psychiatry · June 2014 OBJECTIVE: Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and se ... Full text Link to item Cite

Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan.

Journal Article Hum Brain Mapp · June 2014 As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This ... Full text Open Access Link to item Cite

The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders.

Journal Article Genet Med · February 2014 PURPOSE: The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economica ... Full text Link to item Cite

Applicability of the nonverbal learning disability paradigm for children with 22q11.2 deletion syndrome.

Journal Article J Learn Disabil · 2014 Chromosome 22qll.2 deletion syndrome (22qllDS) is the most common microdeletion in humans. Nonverbal learning disability (NLD) has been used to describe the strengths and deficits of children with 22q11DS, but the applicability of the label for this popula ... Full text Link to item Cite

Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome.

Journal Article J Intellect Disabil Res · January 2014 BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cog ... Full text Link to item Cite

Discrepancies in parent and teacher ratings of social-behavioral functioning of children with chromosome 22q11.2 deletion syndrome: implications for assessment.

Journal Article Am J Intellect Dev Disabil · September 2013 Children with 22q11.2 deletion syndrome exhibit high rates of social-behavioral problems, particularly in the internalizing domain, indicating an area in need of intervention. The current investigation was designed to obtain information regarding parent an ... Full text Link to item Cite

Feasibility and preliminary efficacy data from a computerized cognitive intervention in children with chromosome 22q11.2 deletion syndrome.

Journal Article Res Dev Disabil · September 2013 Children with chromosome 22q11.2 deletion syndrome (22q11DS) are significantly impaired in their academic performance and functionality due to cognitive deficits, especially in attention, memory, and other facets of executive function. Compounding these co ... Full text Link to item Cite

A longitudinal examination of the psychoeducational, neurocognitive, and psychiatric functioning in children with 22q11.2 deletion syndrome.

Journal Article Res Dev Disabil · May 2013 The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnes ... Full text Link to item Cite

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Journal Article Am J Hum Genet · March 7, 2013 Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy rep ... Full text Link to item Cite

Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations.

Journal Article Mol Syndromol · March 2013 The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual fa ... Full text Link to item Cite

Assessment of parental disclosure of a 22q11.2 deletion syndrome diagnosis and implications for clinicians.

Journal Article J Genet Couns · December 2012 Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the d ... Full text Link to item Cite

Altered development of the dorsolateral prefrontal cortex in chromosome 22q11.2 deletion syndrome: an in vivo proton spectroscopy study.

Journal Article Biol Psychiatry · October 15, 2012 BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high risk of schizophrenia. The metabolic basis of the psychologic ... Full text Link to item Cite

Increased corpus callosum volume in children with chromosome 22q11.2 deletion syndrome is associated with neurocognitive deficits and genetic polymorphisms.

Journal Article Eur J Hum Genet · October 2012 Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neuro ... Full text Link to item Cite

Social skills and associated psychopathology in children with chromosome 22q11.2 deletion syndrome: implications for interventions.

Journal Article J Intellect Disabil Res · September 2012 BACKGROUND: Although distinctive neuropsychological impairments have been delineated in children with chromosome 22q11 deletion syndrome (22q11DS), social skills and social cognition remain less well-characterised. OBJECTIVE: To examine social skills and s ... Full text Link to item Cite

Clinical application of exome sequencing in undiagnosed genetic conditions.

Journal Article J Med Genet · June 2012 BACKGROUND: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenoty ... Full text Link to item Cite

Safety of L-proline as a stabilizer for immunoglobulin products (vol 8, pg 169, 2012)

Journal Article EXPERT REVIEW OF CLINICAL IMMUNOLOGY · May 1, 2012 Link to item Cite

Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome.

Journal Article Transl Psychiatry · April 24, 2012 Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our ... Full text Link to item Cite

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge.

Journal Article Am J Med Genet A · September 2011 Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspic ... Full text Link to item Cite

A copy number variation morbidity map of developmental delay.

Journal Article Nat Genet · August 14, 2011 To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate t ... Full text Link to item Cite

Discordance in Diagnoses and Treatment of Psychiatric Disorders in Children and Adolescents with 22q11.2 Deletion Syndrome.

Journal Article Asian J Psychiatr · June 1, 2011 This study examines the rate of utilization of mental health services in children and adolescents with 22q11DS relative to their remarkably high rate of psychiatric disorders and behavior problems. Seventy-two children and adolescents with 22q11DS were par ... Full text Link to item Cite

The role of cephalometry in assessing velopharyngeal dysfunction in velocardiofacial syndrome.

Journal Article Laryngoscope · April 2011 OBJECTIVE: To report our experience with cephalometry in evaluating velopharyngeal dysfunction (VPD) in velocardiofacial syndrome (VCFS) and its utility in assessing the role of cervical spine abnormalities in VPD, prior to surgical correction of VPD. DESI ... Full text Link to item Cite

Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex.

Journal Article Hum Mutat · April 2011 The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is t ... Full text Link to item Cite

Cantú syndrome: report of nine new cases and expansion of the clinical phenotype.

Journal Article Am J Med Genet A · March 2011 Cantú syndrome, a rare disorder of congenital hypertrichosis, characteristic facial anomalies, cardiomegaly, and osteochondrodysplasia was first described in 1982 by Cantú. Twenty-three cases of Cantú syndrome have been reported to date. The pathogenesis o ... Full text Link to item Cite

Reactive lymphoid hyperplasia in association with 22q11.2 deletion syndrome and a BRCA2 mutation.

Journal Article Eur J Med Genet · 2011 We report an adult male with 22q11.2 deletion syndrome and a germline BRCA2 mutation who developed T-cell monoclonal lymphoid proliferation involving the skin and a polyclonal proliferation of a retroperitoneal lymph node without any identifiable infectiou ... Full text Link to item Cite

Epilepsy in trisomy 7 mosaicism: A case report and literature review

Journal Article Journal of Pediatric Neurology · January 1, 2011 Epilepsy is found to be frequently associated with many chromosomal disorders. We describe a 5-year-old boy with recurrent absence seizures, developmental delay, hypomelanosis of Ito, facial asymmetry and mild dysmorphic features that has tissue specific t ... Full text Cite

Pseudometabolic presentation of dystrophinopathy due to a missense mutation.

Journal Article Muscle Nerve · December 2010 Exercise intolerance with myalgia, muscle stiffness, and recurrent rhabdomyolysis due to mutations in the DMD gene can mimic metabolic myopathies leading to delayed or inaccurate diagnoses. In this retrospective chart review, we report 3 unrelated boys wit ... Full text Link to item Cite

Socioeconomic status and psychological function in children with chromosome 22q11.2 deletion syndrome: implications for genetic counseling.

Journal Article J Genet Couns · October 2010 The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in t ... Full text Link to item Cite

COMT and anxiety and cognition in children with chromosome 22q11.2 deletion syndrome.

Journal Article Psychiatry Res · July 30, 2010 The COMT gene is thought to contribute to the cognitive/psychiatric phenotypes in 22q11.2 deletion syndrome. We measured these manifestations against the Val/Met alleles of the COMT gene, in 40 nonpsychotic 22q11DS children. The Val allele was associated w ... Full text Link to item Cite

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.

Journal Article Psychiatry Res · January 30, 2010 Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neuroc ... Full text Link to item Cite

Velocardiofacial syndrome (Chromosome 22q11.2 deletion syndrome) as a model of schizophrenia

Chapter · January 1, 2010 Facts box Velocardiofacial syndrome (VCFS), caused by a heterozygous deletion of chromosome 22q11.2, is associated with congenital anomalies, medical complications, and cognitive impairment. VCFS is associated with an extraordinarily high risk (30%-40%) of ... Full text Cite

Mechanistic approach to understanding psychosis risk in velocardiofacial syndrome

Journal Article Current Pediatric Reviews · August 18, 2009 Velocardiofacial syndrome (VCFS), the most common chromosomal microdeletion syndrome in humans, is caused by a heterozygous deletion of chromosome 22q11.2. With an incidence of 1/2000-1/6000, it is associated with a vast array of abnormalities such as cong ... Full text Cite

Case report: aplasia of the lacrimal and major salivary glands (ALSG).

Journal Article Int J Pediatr Otorhinolaryngol · June 2009 Aplasia of the lacrimal and major salivary glands (ALSG) is a rare, autosomal dominant disorder that is characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary glands. Affected patients may have aplasia or hypoplasia or minimal involv ... Full text Link to item Cite

Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients.

Journal Article Hum Mutat · October 2008 Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. ... Full text Link to item Cite

FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG).

Journal Article Eur J Hum Genet · March 2007 Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant congenital anomaly characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems. Affected individuals present with irritable eyes and dryness of the mouth with ... Full text Link to item Cite

Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region.

Journal Article Hum Mutat · February 2007 Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p. ... Full text Link to item Cite

Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome.

Journal Article Am J Med Genet B Neuropsychiatr Genet · January 5, 2007 22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual-spatial ability, non-verbal reasoning, and planning skills ... Full text Link to item Cite

Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome.

Journal Article Clin Genet · March 2006 Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in ... Full text Link to item Cite

Mosaicism for an FMR1 gene deletion in a fragile X female.

Journal Article Am J Med Genet A · July 15, 2005 Most cases of fragile X syndrome result from expansion of CGG repeats in the FMR1 gene; deletions and point mutations of FMR1 are much less common. Mosaicism for an FMR1 full mutation with a deletion or with a normal allele has been reported in fragile X m ... Full text Link to item Cite

Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome.

Journal Article Neuroimage · April 2004 Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the ... Full text Link to item Cite

Ring chromosome 17: phenotype variation by deletion size.

Journal Article Clin Genet · October 2003 Ring chromosome 17 is a rare cytogenetic abnormality, with 12 previous reports in the literature. Some have a relatively mild phenotype characterized by seizures, mental retardation, skin changes and short stature. Other patients have Miller-Dieker syndrom ... Full text Link to item Cite

Vincristine-induced neuropathy as the initial presentation of charcot-marie-tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Journal Article J Pediatr Hematol Oncol · April 2003 PURPOSE: After profound peripheral neurotoxicity during induction chemotherapy for acute lymphoblastic leukemia (ALL) in the index patient with Charcot-Marie-Tooth hereditary neuropathy (CMT), study coordinators of the Pediatric Oncology Group (POG) front- ... Full text Link to item Cite

ENVIRONMENTAL ETIOLOGIES OF OROFACIAL CLEFTING AND CRANIOSYNOSTOSIS

Chapter · January 1, 2003 In this chapter, environmental factors that are etiologically related to orofacial clefts and craniosynostoses are reviewed. We include a discussion of gene-environment interactions, which are currently incompletely understood in most cases. We provide sum ... Full text Cite

Further evidence of a tumor suppressor gene at 7q22 in malignant myeloid diseases.

Conference AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2002 Link to item Cite

Ectodermal dysplasia: otolaryngologic manifestations and management.

Journal Article Laryngoscope · June 2002 OBJECTIVE: To present the otolaryngologic manifestations and management of 12 patients with the rare presentation of ectodermal dysplasia. STUDY DESIGN: A retrospective chart review combined with a patient evaluation by the specialties of genetics, dermato ... Full text Link to item Cite

A combination of physical examination and ECG detects the majority of hemodynamically significant heart defects in neonates with Down syndrome.

Journal Article Am J Med Genet · March 15, 2002 Echocardiography has become the method of choice in the diagnosis of a congenital heart defect (CHD) in neonates with Down syndrome. The most compelling argument for diagnosis of CHD in the neonatal period is the need for early surgical intervention (ideal ... Full text Link to item Cite

Vasomotor instability in chromosome 22q11 deletion.

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2001 Link to item Cite

Further characterization of odontotrichomelic syndrome.

Conference AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2001 Link to item Cite

Reynolds acrofacial dysostosis: Report of an additional family.

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2001 Link to item Cite

Prenatal diagnosis of complete sole trisomy 1q.

Journal Article Prenat Diagn · June 2001 The prenatal diagnosis of a complete trisomy of the long arm of chromosome 1 is reported. Major ultrasound findings included: nuchal thickening, bi-temporal narrowing, a single choroid plexus cyst, and mild ventriculomegaly. There was a mass in the chest a ... Full text Link to item Cite

Maternal homozygosity for the common MTHFR mutation as a potential risk factor for offspring with limb defects.

Journal Article Am J Med Genet · April 15, 2001 A common mutation, C677T, in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene leads to altered homocysteine metabolism, and has been associated with the occurrence of neural tube defects (NTD). Administration of folic acid decreases this risk. The ... Full text Link to item Cite

Does every neonate with Down syndrome need an echocardiogram?

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 2000 Link to item Cite

A unique form of mental retardation with a distinctive phenotype maps to Xq26-q27.

Journal Article Am J Hum Genet · February 2000 We report a novel X-linked mental retardation (XLMR) syndrome, with characteristic facial dysmorphic features, segregating in a large North Carolina family. Only males are affected, over four generations. Clinical findings in the seven living affected male ... Full text Link to item Cite

Chromosome 7q22 is a likely site of a tumor suppressor gene in malignant myeloid diseases.

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · October 1, 1999 Link to item Cite

Partial duplication of 4q12q13 leads to a mild phenotype.

Journal Article Am J Med Genet · September 3, 1999 We report on the second case of duplication (4)(q12q13) with microcephaly, mental retardation, and minor facial anomalies. Duplications involving the distal region of chromosome 4q are well described and share common clinical findings. However, phenotypic ... Link to item Cite

Genetic heterogeneity of gingival fibromatosis on chromosome 2p.

Journal Article J Med Genet · September 1999 Gingival fibromatosis (GF) occurs in several genetic forms as a simple Mendelian trait, in malformation syndromes, and in some chromosomal disorders. Specific genes responsible for GF have not been identified. An autosomal dominant form of hereditary gingi ... Link to item Cite

A further case of choanal atresia in the deletion (9p) syndrome.

Journal Article Am J Med Genet · December 4, 1998 Link to item Cite

Water intoxication in a patient with the Prader-Willi syndrome treated with desmopressin for nocturnal enuresis.

Journal Article J Urol · February 1997 PURPOSE: We report on a girl with the Prader-Willi syndrome who received desmopressin for nocturnal enuresis, and water intoxication developed after she ingested a large amount of fluid. MATERIALS AND METHODS: The patient received 10 mg. desmopressin at be ... Link to item Cite

Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.

Journal Article Am J Hum Genet · June 1996 It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen ... Link to item Cite

Constellation of congenital abnormalities in an infant: a new syndrome or tissue-specific mosaicism for trisomy 18?

Journal Article Am J Med Genet · March 1, 1996 A newborn infant born to consanguineous (first cousin) parents was noted to have complex congenital heart defect and minor anomalies suggestive of trisomy 18. Blood lymphocyte and skin fibroblast karyotypes were normal. He died in the neonatal period of po ... Full text Link to item Cite

Vascular ring leading to tracheoesophageal compression in a patient with Rubinstein-Taybi syndrome.

Journal Article Clin Genet · December 1995 Mediastinal vascular rings cause tracheoesophageal obstruction, resulting in respiratory symptoms and dysphagia in children. Although a large number of children with Rubinstein-Taybi syndrome have frequent respiratory infections and feeding difficulties, t ... Full text Link to item Cite

Loss of chromosomes 22 and 14 in the malignant progression of meningiomas. A comparative study of fluorescence in situ hybridization (FISH) and standard cytogenetic analysis.

Journal Article Cancer Genet Cytogenet · December 1995 The majority of meningiomas are classified as typical and have a relatively benign course. However, approximately 10% are diagnosed as atypical, anaplastic, or malignant and have a worse prognosis. The genetic differences between the typical and higher gra ... Full text Link to item Cite

Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases.

Journal Article J Med Genet · June 1995 A new neuroectodermal syndrome (designated CHIME syndrome) was described in 1983 with a total of four patients reported, it is presumed to be an autosomal recessive disorder because of recurrence in sibs. The main features include ocular colobomas, congeni ... Full text Link to item Cite

Absent pituitary gland in two brothers with an oral-facial-digital syndrome resembling OFDS II and VI: a new type of OFDS?

Journal Article Am J Med Genet · May 22, 1995 The oral-facial-digital syndromes (OFDS) comprise a group of heterogeneous genetic disorders. Considerable clinical overlap exists within the nine described types [Toriello, Clin Dysmorph 2:95-105, 1993], and with other entities such as Pallister-Hall (PH) ... Full text Link to item Cite

Interphase fluorescence in situ hybridization for trisomy 12 on archival ovarian sex cord-stromal tumors.

Journal Article Gynecol Oncol · December 1994 Trisomy 12 is a nonrandom chromosomal abnormality found in a large proportion of ovarian sex cord-stromal tumors (OSCTs), including thecoma-fibromas (TFs) and granulosa cell tumors (GCTs). The prognostic significance of trisomy 12 in these tumors, however, ... Full text Link to item Cite

Malignant rhabdoid tumor of the kidney: involvement of chromosome 22.

Journal Article Genes Chromosomes Cancer · May 1994 Cytogenetic and molecular studies have demonstrated that involvement of 22q is a non-random finding in malignant rhabdoid tumors (MRTs) of the brain. We present an MRT of the kidney with the karyotype 47,XY, + i(1)(q10), der(8)t(8;22)(q12;q11.2),der(22)t(8 ... Full text Link to item Cite

Choanal atresia in a patient with the deletion (9p) syndrome.

Journal Article Am J Med Genet · January 1, 1994 We report on a child with choanal atresia and deletion 9p. A review of the literature documented one previous instance of choanal atresia in a patient with del(9p). Choanal atresia may be part of the spectrum of malformations in the deletion (9p) syndrome ... Full text Link to item Cite

INTERPHASE CYTOGENETIC ANALYSIS FOR TRISOMY-12 IN OVARIAN SEX CORD-STROMAL TUMORS

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · September 1, 1993 Link to item Cite

COMPARATIVE FLUORESCENT IN-SITU HYBRIDIZATION AND STANDARD CYTOGENETIC ANALYSIS IN MENINGIOMAS

Journal Article AMERICAN JOURNAL OF HUMAN GENETICS · September 1, 1993 Link to item Cite

MALIGNANT RHABDOID TUMOR OF THE KIDNEY - INVOLVEMENT OF CHROMOSOME-22

Journal Article CYTOGENETICS AND CELL GENETICS · January 1, 1993 Link to item Cite