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

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. Patho...

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Published in:	American journal of medical genetics. Part A Vol. 191; no. 8; pp. 2113 - 2131
Main 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.
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-08-2023 Wiley Subscription Services, Inc
Subjects:	CdLS Cell Cycle Proteins - genetics Cohesin Cornelia de Lange Syndrome De Lange syndrome De Lange Syndrome - diagnosis De Lange Syndrome - genetics De Lange Syndrome - pathology Decades Developmental disabilities Gene regulation Genetic Association Studies genome Genomic analysis Genomics Genotype & phenotype Genotypes HDAC8 Histone Deacetylases - genetics Humans Hypertrichosis Mutation NIPBL Nuclear Proteins - genetics Phenotype Phenotypes RAD21 Regulatory proteins Repressor Proteins - genetics SMC1A SMC3 transcription Transcription Factors - genetics Transcriptional Elongation Factors - genetics genome NIPBL cohesin transcription RAD21 CdLS Cornelia de Lange Syndrome HDAC8 SMC1A SMC3
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors’ Contributions Maninder Kaur: designed and performed the experiments, processed the experimental data, performed the analysis collected and analyzed data, drafted and wrote the paper with input from all authors, designed the figures. Justin Blair: Contributed data acquisition and data analysis tools and performed the manuscript’s analysis and writing. Batsal Devkota: contributed data acquisition, and data analysis tools and performed the analysis. Sierra Fortunato: sample and data collection. Dinah Clark: sample and data collection. Audrey Lawrence: data collection. Jiwoo Kim: whole genome sequencing data analysis. Wonwook Do: performed the experiments and analyzed the data. Benjamin Semeo: performed the experiments and analyzed the data. Olivia Katz: performed the experiments and analyzed the data. Devanshi Mehta: performed the experiments and analyzed the data. Nobuko Yamamoto: performed whole genome sequencing data analysis. Emma Schindler: data analysis and helped write the manuscript. Zayd Al Rawi: data analysis. Nina Wallace: performed the experiments and analyzed the data. Jonathan J. Wilde: performed the experiments and analyzed the data. Jennifer McCallum: performed the experiments and analyzed the data. Jinglan Liu: performed the experiments and analyzed the data., Dongbin Xu: performed the experiments and analyzed the data. Marie Jackson: sample and data collection. Stefan Rentas: performed RNAseq and data analysis. Ahmad Abou Tayoun,: performed RNAseq and data analysis. Zhang Zhe: processed the experimental data, and performed the analysis. Omar Abdul-Rahman: contributed patient information and samples. Bill Allen: contributed patient information and samples. Moris A Angula: contributed patient information and samples. Kwame Anyane-Yeboa: contributed patient information and samples. Jesús Argente: contributed patient information and samples. Pamela H Arn: contributed patient information and samples. Linlea Armstrong: contributed patient information and samples. Lina Basel-Salmon: contributed patient information and samples. Gareth Baynam: contributed patient information and samples. Lynne M. Bird: contributed patient information and samples, reviewing and editing of manuscript: Daniel Bruegger: contributed patient information and samples. Gaik-Siew Ch’ng: contributed patient information and samples. David Chitayat: contributed patient information and samples. Robin Clark: contributed patient information and samples. Gerald F. Cox: contributed patient information and samples. Usha Dave: contributed patient information and samples. Elfrede DeBaere: contributed patient information and samples. Michael Field: contributed patient information and samples. John M Graham: contributed patient information and samples. Jr, Karen W. Gripp: contributed patient information and samples. Robert Greenstein: contributed patient information and samples. Neerja Gupta: contributed patient information and samples. Randy Heidenreich: contributed patient information and samples, Jodi Hoffman: contributed patient information and samples. Robert J Hopkin: contributed patient information and samples. Kenneth L. Jones: contributed patient information and samples. Marilyn C. Jones: contributed patient information and samples. Ariana Kariminejad: contributed patient information and samples. Jillene Kogan: contributed patient information and samples. Baiba Lace: contributed patient information and samples. Julian Leroy: contributed patient information and samples. Sally Ann Lynch: contributed patient information and samples. Marie McDonald: contributed patient information and samples. Kirsten Meagher: contributed patient information and samples. Nancy Mendelsohn: contributed patient information and samples. Ieva Micule: contributed patient information and samples. John Moeschler: contributed patient information and samples. Sheela Nampoothiri: contributed patient information and samples. Kaoru Ohashi: contributed patient information and samples. Cynthia M Powell: contributed patient information and samples. Subhadra Ramanathan: contributed patient information and samples. Salmo Raskin: contributed patient information and samples. Elizabeth Roeder: contributed patient information and samples. Marlene Rio: contributed patient information and samples. Alan F. Rope: contributed patient information and samples. Karan Sangha: contributed patient information and samples. Angela E Scheuerle: contributed patient information and samples. Adele Schneider: contributed patient information and samples. Stavit Shalev: contributed patient information and samples. Victoria Siu: contributed patient information and samples. Rosemarie Smith: contributed patient information and samples. Cathy Stevens: contributed patient information and samples. Tinatin Tkemaladze: contributed patient information and samples. John Toimie: contributed patient information and samples. Helga Toriello: contributed patient information and samples. Anne Turner: contributed patient information and samples. Patricia G. Wheeler: contributed patient information and samples. Susan M White: contributed patient information and samples. Terri Young: contributed patient information and samples, Kathleen M Loomes: contributed patient information and samples, review and editing of the manuscript. Mary Pipan: contributed patient information and samples, review, and editing of the manuscript. Ann Tokay Harrington: contributed patient information and samples, Elaine Zackai: contributed patient information and samples. Ramakrishnan Rajagopalan: whole genome sequencing data analysis. Laura Conlin: contributed data acquisition, and data analysis tools and performed the analysis. Matthew A. Deardorff: Data collection, analysis and interpretation of results, contributed patient information and samples, performed experiments, reviewed and editing of manuscript. Deborah McEldrew: performed experiments and data analysis. Juan Pie: contributed patient information and samples. Feliciano Ramos: data analysis and data sharing. Antonio Musio: data sharing. Tonie Kline: contributed patient information and samples, review and editing of manuscript. Kosuke Izumi: contributed patient information and samples, performed the experiments and analyzed the data. Sarah E. Raible: sample and data collection, manuscript review and editing, administration. Ian D. Krantz: study conception and design, drafting and writing the manuscript, data curation, methodology, project administration, acquisition, analysis, and interpretation of data.
ISSN:	1552-4825 1552-4833 1552-4833
DOI:	10.1002/ajmg.a.63247