Skip to main content
Journal cover image

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

Publication ,  Journal Article
Schoch, K; Meng, L; Szelinger, S; Bearden, DR; Stray-Pedersen, A; Busk, OL; Stong, N; Liston, E; Cohn, RD; Scaglia, F; Rosenfeld, JA; Bali, D ...
Published in: Am J Hum Genet
February 2, 2017

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

February 2, 2017

Volume

100

Issue

2

Start / End Page

343 / 351

Location

United States

Related Subject Headings

  • Spasms, Infantile
  • Repressor Proteins
  • Phenotype
  • Pedigree
  • Neoplasm Proteins
  • Mutation, Missense
  • Microcephaly
  • Male
  • Magnetic Resonance Imaging
  • Intellectual Disability
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Schoch, K., Meng, L., Szelinger, S., Bearden, D. R., Stray-Pedersen, A., Busk, O. L., … Shashi, V. (2017). A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet, 100(2), 343–351. https://doi.org/10.1016/j.ajhg.2016.12.013
Schoch, Kelly, Linyan Meng, Szabolcs Szelinger, David R. Bearden, Asbjorg Stray-Pedersen, Oyvind L. Busk, Nicholas Stong, et al. “A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.Am J Hum Genet 100, no. 2 (February 2, 2017): 343–51. https://doi.org/10.1016/j.ajhg.2016.12.013.
Schoch K, Meng L, Szelinger S, Bearden DR, Stray-Pedersen A, Busk OL, et al. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet. 2017 Feb 2;100(2):343–51.
Schoch, Kelly, et al. “A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.Am J Hum Genet, vol. 100, no. 2, Feb. 2017, pp. 343–51. Pubmed, doi:10.1016/j.ajhg.2016.12.013.
Schoch K, Meng L, Szelinger S, Bearden DR, Stray-Pedersen A, Busk OL, Stong N, Liston E, Cohn RD, Scaglia F, Rosenfeld JA, Tarpinian J, Skraban CM, Deardorff MA, Friedman JN, Akdemir ZC, Walley N, Mikati MA, Kranz PG, Jasien J, McConkie-Rosell A, McDonald M, Wechsler SB, Freemark M, Kansagra S, Freedman S, Bali D, Millan F, Bale S, Nelson SF, Lee H, Dorrani N, UCLA Clinical Genomics Center, Undiagnosed Diseases Network, Goldstein DB, Xiao R, Yang Y, Posey JE, Martinez-Agosto JA, Lupski JR, Wangler MF, Shashi V. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet. 2017 Feb 2;100(2):343–351.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

February 2, 2017

Volume

100

Issue

2

Start / End Page

343 / 351

Location

United States

Related Subject Headings

  • Spasms, Infantile
  • Repressor Proteins
  • Phenotype
  • Pedigree
  • Neoplasm Proteins
  • Mutation, Missense
  • Microcephaly
  • Male
  • Magnetic Resonance Imaging
  • Intellectual Disability