Yuan, Bo, Neira, Juanita, Pehlivan, Davut, Santiago-Sim, Teresa, Song, Xiaofei, Rosenfeld, Jill, Posey, Jennifer E. ORCID: 0000-0003-4814-6765, Patel, Vipulkumar, Jin, Weihong, Adam, Margaret P., Baple, Emma L., Dean, John, Fong, Chin-To, Hickey, Scott E., Hudgins, Louanne, Leon, Eyby ORCID: 0000-0002-1852-2849, Madan-Khetarpal, Suneeta, Rawlins, Lettie, Rustad, Cecilie F., Stray-Pedersen, Asbjorg, Tveten, Kristian, Wenger, Olivia, Diaz, Jullianne, Jenkins, Laura, Martin, Laura, McGuire, Marianne, Pietryga, Marguerite, Ramsdell, Linda, Slattery, Leah, Abid, Farida, Bertuch, Alison A., Grange, Dorothy, Immken, LaDonna, Schaaf, Christian P., Van Esch, Hilde, Bi, Weimin, Cheung, Sau Wai, Breman, Amy M., Smith, Janice L., Shaw, Chad, Crosby, Andrew H., Eng, Christine, Yang, Yaping, Lupski, James R., Xiao, Rui and Liu, Pengfei ORCID: 0000-0002-4177-709X (2019). Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. Genet. Med., 21 (3). S. 663 - 676. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0366

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Abstract

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. Results: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Yuan, BoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neira, JuanitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pehlivan, DavutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santiago-Sim, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Song, XiaofeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenfeld, JillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Posey, Jennifer E.UNSPECIFIEDorcid.org/0000-0003-4814-6765UNSPECIFIED
Patel, VipulkumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jin, WeihongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, Margaret P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baple, Emma L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dean, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fong, Chin-ToUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hickey, Scott E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hudgins, LouanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leon, EybyUNSPECIFIEDorcid.org/0000-0002-1852-2849UNSPECIFIED
Madan-Khetarpal, SuneetaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rawlins, LettieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rustad, Cecilie F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stray-Pedersen, AsbjorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tveten, KristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenger, OliviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz, JullianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenkins, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuire, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietryga, MargueriteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramsdell, LindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Slattery, LeahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abid, FaridaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertuch, Alison A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grange, DorothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Immken, LaDonnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Esch, HildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bi, WeiminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheung, Sau WaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Breman, Amy M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Janice L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaw, ChadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crosby, Andrew H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eng, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, YapingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lupski, James R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xiao, RuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, PengfeiUNSPECIFIEDorcid.org/0000-0002-4177-709XUNSPECIFIED
URN: urn:nbn:de:hbz:38-155591
DOI: 10.1038/s41436-018-0085-6
Journal or Publication Title: Genet. Med.
Volume: 21
Number: 3
Page Range: S. 663 - 676
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-LANGE-SYNDROME; INTELLECTUAL DISABILITY; DEVELOPMENTAL DELAY; MUTATIONS CAUSE; COHESIN; STAG2; NIPBL; VARIANTS; COMPLEX; PROTEINSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15559

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