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Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Publication ,  Journal Article
Kaur, M; Blair, J; Devkota, B; Fortunato, S; Clark, D; Lawrence, A; Kim, J; Do, W; Semeo, B; Katz, O; Mehta, D; Yamamoto, N; Schindler, E ...
Published in: Am J Med Genet A
August 2023

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

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Published In

Am J Med Genet A

DOI

EISSN

1552-4833

Publication Date

August 2023

Volume

191

Issue

8

Start / End Page

2113 / 2131

Location

United States

Related Subject Headings

  • Transcriptional Elongation Factors
  • Transcription Factors
  • Repressor Proteins
  • Phenotype
  • Nuclear Proteins
  • Mutation
  • Humans
  • Histone Deacetylases
  • Genomics
  • Genetic Association Studies
 

Citation

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Chicago
ICMJE
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Kaur, M., Blair, J., Devkota, B., Fortunato, S., Clark, D., Lawrence, A., … Krantz, I. D. (2023). Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms. Am J Med Genet A, 191(8), 2113–2131. https://doi.org/10.1002/ajmg.a.63247
Kaur, Maninder, Justin Blair, Batsal Devkota, Sierra Fortunato, Dinah Clark, Audrey Lawrence, Jiwoo Kim, et al. “Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.Am J Med Genet A 191, no. 8 (August 2023): 2113–31. https://doi.org/10.1002/ajmg.a.63247.
Kaur M, Blair J, Devkota B, Fortunato S, Clark D, Lawrence A, et al. Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms. Am J Med Genet A. 2023 Aug;191(8):2113–31.
Kaur, Maninder, et al. “Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.Am J Med Genet A, vol. 191, no. 8, Aug. 2023, pp. 2113–31. Pubmed, doi:10.1002/ajmg.a.63247.
Kaur M, Blair J, Devkota B, Fortunato S, Clark D, Lawrence A, Kim J, Do W, Semeo B, Katz O, Mehta D, Yamamoto N, Schindler E, Al Rawi Z, Wallace N, Wilde JJ, McCallum J, Liu J, Xu D, Jackson M, Rentas S, Tayoun AA, Zhe Z, Abdul-Rahman O, Allen B, Angula MA, Anyane-Yeboa K, Argente J, Arn PH, Armstrong L, Basel-Salmon L, Baynam G, Bird LM, Bruegger D, Ch’ng G-S, Chitayat D, Clark R, Cox GF, Dave U, DeBaere E, Field M, Graham JM, Gripp KW, Greenstein R, Gupta N, Heidenreich R, Hoffman J, Hopkin RJ, Jones KL, Jones MC, Kariminejad A, Kogan J, Lace B, Leroy J, Lynch SA, McDonald M, Meagher K, Mendelsohn N, Micule I, Moeschler J, Nampoothiri S, Ohashi K, Powell CM, Ramanathan S, Raskin S, Roeder E, Rio M, Rope AF, Sangha K, Scheuerle AE, Schneider A, Shalev S, Siu V, Smith R, Stevens C, Tkemaladze T, Toimie J, Toriello H, Turner A, Wheeler PG, White SM, Young T, Loomes KM, Pipan M, Harrington AT, Zackai E, Rajagopalan R, Conlin L, Deardorff MA, McEldrew D, Pie J, Ramos F, Musio A, Kline AD, Izumi K, Raible SE, Krantz ID. Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms. Am J Med Genet A. 2023 Aug;191(8):2113–2131.
Journal cover image

Published In

Am J Med Genet A

DOI

EISSN

1552-4833

Publication Date

August 2023

Volume

191

Issue

8

Start / End Page

2113 / 2131

Location

United States

Related Subject Headings

  • Transcriptional Elongation Factors
  • Transcription Factors
  • Repressor Proteins
  • Phenotype
  • Nuclear Proteins
  • Mutation
  • Humans
  • Histone Deacetylases
  • Genomics
  • Genetic Association Studies