Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype–phenotype correlations and common mechanisms
Authors: Kaur Maninder , Blair Justin , Devkota Batsal , Fortunato Sierra , Clark Dinah , Lawrence Audrey , Kim Jiwoo , Do Wonwook , Semeo Benjamin , Katz Olivia , Mehta Devanshi , Yamamoto Nobuko , Schindler Emma , Al Rawi Zayd , Wallace Nina , Wilde Jonathan J. , McCallum Jennifer , Liu Jinglan , Xu Dongbin , Jackson Marie , Rentas Stefan , Tayoun Ahmad Abou , Zhe Zhang , Abdul‐Rahman Omar , Allen Bill , Angula Moris A. , Anyane‐Yeboa Kwame , Argente Jesús , Arn Pamela H. , Armstrong Linlea , Basel‐Salmon Lina , Baynam Gareth , Bird Lynne M. , Bruegger Daniel , Ch'ng Gaik‐Siew , Chitayat David , Clark Robin , Cox Gerald F. , Dave Usha , DeBaere Elfrede , Field Michael , Graham Jr John M. , Gripp Karen W. , Greenstein Robert , Gupta Neerja , Heidenreich Randy , Hoffman Jodi , Hopkin Robert J. , Jones Kenneth L. , Jones Marilyn C. , Kariminejad Ariana , Kogan Jillene , Lace Baiba , Leroy Julian , Lynch Sally Ann , McDonald Marie , Meagher Kirsten , Mendelsohn Nancy , Micule Ieva , Moeschler John , Nampoothiri Sheela , Ohashi Kaoru , Powell Cynthia M. , Ramanathan Subhadra , Raskin Salmo , Roeder Elizabeth , Rio Marlene , Rope Alan F. , Sangha Karan , Scheuerle Angela E. , Schneider Adele , Shalev Stavit , Siu Victoria , Smith Rosemarie , Stevens Cathy , Tkemaladze Tinatin , Toimie John , Toriello Helga , Turner Anne , Wheeler Patricia G. , White Susan M. , Young Terri , Loomes Kathleen M. , Pipan Mary , Harrington Ann Tokay , Zackai Elaine , Rajagopalan Ramakrishnan , Conlin Laura , Deardorff Matthew A. , McEldrew Deborah , Pie Juan , Ramos Feliciano , Musio Antonio , Kline Antonie D. , Izumi Kosuke , Raible Sarah E. , Krantz Ian D. 
Published: June 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.