Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Yuan, Bo; Neira, Juanita; Pehlivan, Davut; Santiago‐Sim, Teresa; Song, Xiaofei; Rosenfeld, Jill A.; Posey, Jennifer E.; Patel, Vipulkumar; Jin, Weihong; Adam, Margaret P; Baple, Emma L.; Dean, John; Fong, Chin‐To; Hickey, Scott E.; Hudgins, Louanne; Leon, Eyby; Madan‐Khetarpal, Suneeta; Rawlins, Lettie E; Rustad, Cecilie F.; Stray-Pedersen, Asbjørg; Tveten, Kristian; Wenger, Olivia; Diaz, Jullianne; Jenkins, Laura; Martin, Laura S.; McGuire, Marianne; Pietryga, Marguerite; Ramsdell, Linda; Slattery, Leah; Abid, Farida; Bertuch, Alison A.; Grange, Dorothy K.; Immken, LaDonna; Schaaf, Christian P.; Esch, Hilde Van; Bi, Weimin; Cheung, Sau Wai; Breman, Amy M.; Smith, Janice; Shaw, Chad A.; Crosby, Andrew H.; Eng, Christine M.; Yang, Yaping; Lupski, James R.; Xiao, Rui; Liu, Pengfei

doi:10.1038/s41436-018-0085-6

Cited by 61 publications

(62 citation statements)

References 45 publications

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“…Of the 49 cases, 24 are new. Twentyfive were previously published (Ansari et al 2014;Bonora et al 2015;Boyle et al 2017;Deardorff et al 2012;Dorval et al 2019;Gudmundsson et al 2018;Kruszka et al 2019;Lee et al 2014;Martinez et al 2017;McBrien et al 2008;Minor et al 2014;Yuan et al 2019), and for 19 of these clinical data could be updated (Table 1). Patients originated from Australia, Belgium, Canada, Denmark, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, Turkey, United Kingdom and United States.…”

Section: Resultsmentioning

confidence: 99%

“…RAD21 has been implicated in additional processes including mediation of epigenetic silencing and induction of apoptosis (Fisher et al 2017;Pati et al 2002). Variants in genes encoding various structural or functional components of the cohesin complex, including RAD21, SMC1A, SMC3, BRD4, STAG1/2, NIPBL, HDAC8, WAPL, ANKRD11 and in single individuals PDS5A and ESPL1, have been implicated in Cornelia de Lange Syndrome (CdLS) (Ansari et al 2014;Kline et al 2018;Woods et al 2014;Yuan et al 2019). RAD21 spans ~ 29 Kb and has 14 exons (13 coding, 1 noncoding) that together encode a protein of 631 amino acids (McKay et al 1996). 1 3 RAD21 variants are found in a minority of CdLS patients.…”

Section: Introductionmentioning

confidence: 99%

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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.Zeynep Tümer and Raoul C. Hennekam contributed equally.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

et al. 2020

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“…Cornelia de Lange syndrome (CdLS, MIM 122470, 300590, 300882, 610759, 614701) is a clinically recognizable genetic disorder characterized by severe growth restriction, developmental delay, a distinctive facial appearance including synophrys, highly arched eyebrows, long eyelashes and a long smooth philtrum, and limb abnormalities. Pathogenic variants in NIPBL , HDAC8 , SMC1A , SMC3 , and RAD21 are associated with CdLS (Deardorff et al, ; Deardorff, Bando, et al, ; Deardorff, Wilde, et al, ; Krantz et al, ; Musio et al, ; Tonkin, Wang, Lisgo, Bamshad, & Strachan, ; Yuan et al, ). The encoded proteins are all components of, or interact with, the cohesin complex, which is responsible for regulating sister chromatid cohesion and segregation, as well as maintaining genomic stability (Cucco & Musio, ).…”

Section: Introductionmentioning

confidence: 99%

“…Of note, genomic rearrangements involving NIPBL , deletion CNV, have also been reported in some CdLS patients (Pehlivan et al, ). Variants in different “cohesinopathy genes” can have varying severity of clinical phenotypes (Yuan et al, ). Despite identification of multiple genes associated with CdLS, over 25% of individuals with a clinical diagnosis have negative genetic testing (Gil‐Rodríguez et al, ), suggesting the existence of additional yet unidentified genes or yet undefined mechanisms of disease.…”

Section: Introductionmentioning

confidence: 99%

Whole‐genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome

Duvdevani

Pettersson

Eisfeldt

et al. 2020

American J of Med Genetics Pt A

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Clinical laboratory diagnostic evaluation of the genomes of children with suspected genetic disorders, including chromosomal microarray and exome sequencing, cannot detect copy number neutral genomic rearrangements such as inversions, balanced translocations, and complex chromosomal rearrangements (CCRs). We describe an infant with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) in whom chromosome analysis revealed a de novo complex balanced translocation, 46,XY,t(5;7;6) (q11.2;q32;q13)dn. Subsequent molecular characterization by whole-genome sequencing (WGS) identified 23 breakpoints, delineating segments derived from four chromosomes (5;6;7;21) in ancestral or inverted orientation. One of the breakpoints disrupted a known CdLS gene, NIPBL. Further investigation revealed paternal origin of the CCR allele, clustering of the breakpoint junctions, and molecular repair signatures suggestive of a single catastrophic event. Notably, very short DNA segments (25 and 41 bp) were included in the reassembled chromosomes, lending additional support that the DNA repair machinery can detect and repair such segments. Interestingly, there was an independent paternally derived miniscule complex rearrangement, possibly predisposing to subsequent genomic instability. In conclusion, we report a CCR causing a monogenic Mendelian disorder, urging WGS analysis of similar unsolved cases with suspected Mendelian disorders. Breakpoint analysis allowed for identification of the underlying molecular diagnosis and implicated chromoanagenesis in CCR formation.

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“…Mutations in the STAG2 gene encoding SA2 cause intellectual and growth deficits overlapping those seen in cohesinopathies caused by mutations in NIPBL or cohesin subunit genes (Mullegama et al 2017, Soardi et al 2017, Mullegama et al 2018, Yuan et al 2018. Individuals with BRD4 mutations display similar birth defects, and BRD4 and NIPBL co-localize at enhancers (Olley et al 2018).…”

Section: Parallels With Vertebrate Cohesinmentioning

confidence: 99%

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

Pherson

Misulovin

Gause

et al. 2019

Preprint

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Cohesin consists of the Smc1-Smc3-Rad21 tripartite ring and the SA protein that interacts with Rad21. The Nipped-B protein loads cohesin topologically around chromosomes to mediate sister chromatid cohesion and facilitate long-range control of gene transcription. It is largely unknown how Nipped-B and cohesin associate specifically with gene promoters and transcriptional enhancers, or how sister chromatid cohesion is established. Here we use genome-wide chromatin immunoprecipitation in Drosophila cells to show that SA and the Fs(1)h (BRD4) BET domain protein help recruit Nipped-B and cohesin to enhancers and DNA replication origins, while the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 to promoters. All enhancers and their neighboring promoters are close to DNA replication origins and bind SA with proportional levels of cohesin subunits. Most promoters are far from origins and lack SA, but bind Nipped-B and Rad21 with sub-proportional amounts of Smc1, indicating that they bind SA-deficient cohesin part of the time. Genetic data confirm that Nipped-B and Rad21 function together with Fs(1)h in vivo to facilitate Drosophila development. These findings demonstrate that Nipped-B and cohesin are differentially targeted to enhancers and promoters and suggest models for how SA and DNA replication help establish sister chromatid cohesion and facilitate enhancer-promoter communication. They indicate that SA is not an obligatory cohesin subunit but a factor that controls cohesin location on chromosomes.

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Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Abstract: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Cited by 61 publications

References 45 publications

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Whole‐genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome

Cohesin occupancy and composition at enhancers and promoters are linked to DNA replication origin proximity inDrosophila

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