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

2023; Wiley; Volume: 191; Issue: 8 Linguagem: Inglês

10.1002/ajmg.a.63247

1552-4833

Maninder Kaur, Justin Blair, Batsal Devkota, Sierra Fortunato, Dinah Clark, Audrey Lawrence, Jiwoo Kim, Wonwook Do, Benjamin Semeo, Olivia Katz, Devanshi Mehta, Nobuko Yamamoto, Emma Schindler, Zayd Al Rawi, Nina Wallace, Jonathan J. Wilde, Jennifer McCallum, Jinglan Liu, Dongbin Xu, Marie Jackson, Stefan Rentas, Ahmad Abou Tayoun, Zhe Zhang, Omar Abdul‐Rahman, Bill Allen, Moris A. Angula, Kwame Anyane‐Yeboa, Jesús Argente, Pamela Arn, Linlea Armstrong, Lina Basel‐Salmon, Gareth Baynam, Lynne M. Bird, Daniel E. Bruegger, Gaik‐Siew Ch'ng, David Chitayat, Robin D. Clark, Gerald F. Cox, Usha Dave, Elfrede DeBaere, Michael Field, John M. Graham, Karen W. Gripp, Robert M. Greenstein, Neerja Gupta, Randy Heidenreich, Jodi D. Hoffman, Robert J. Hopkin, Kenneth Lyons Jones, Marilyn C. Jones, Ariana Kariminejad, Jillene Kogan, Baiba Lāce, J. G. Leroy, Sally Ann Lynch, Marie McDonald, Kirsten Meagher, Nancy J. Mendelsohn, Ieva Mičule, John B. Moeschler, Sheela Nampoothiri, Kaoru Ohashi, Cynthia M. Powell, Subhadra Ramanathan, Salmo Raskin, Elizabeth Roeder, Marlène Rio, Alan F. Rope, Karan Sangha, Angela E. Scheuerle, Adele Schneider, Stavit A. Shalev, Victoria Mok Siu, Rosemarie Smith, Cathy A. Stevens, Tinatin Tkemaladze, John Toimie, Helga V. Toriello, Anne‐Marie W. Turner, Patricia G. Wheeler, Susan M. White, Terri L. Young, Kathleen M. Loomes, Mary Pipan, Ann T. Harrington, Elaine H. Zackai, Ramakrishnan Rajagopalan, Laura K. Conlin, Matthew A. Deardorff, Deborah McEldrew, Juan Pié, Feliciano J. Ramos, Antonio Musio, Antonie D. Kline, Kosuke Izumi, Sarah E. Raible, Ian D. Krantz,

Genomic variations and chromosomal abnormalities

Abstract 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.