TY - JOUR
T1 - Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies
AU - DDD Study
AU - Yuan, Bo
AU - Neira, Juanita
AU - Pehlivan, Davut
AU - Santiago-Sim, Teresa
AU - Song, Xiaofei
AU - Rosenfeld, Jill
AU - Posey, Jennifer E.
AU - Patel, Vipulkumar
AU - Jin, Weihong
AU - Adam, Margaret P.
AU - Baple, Emma L.
AU - Dean, John
AU - Fong, Chin To
AU - Hickey, Scott E.
AU - Hudgins, Louanne
AU - Leon, Eyby
AU - Madan-Khetarpal, Suneeta
AU - Rawlins, Lettie
AU - Rustad, Cecilie F.
AU - Stray-Pedersen, Asbjørg
AU - Tveten, Kristian
AU - Wenger, Olivia
AU - Diaz, Jullianne
AU - Jenkins, Laura
AU - Martin, Laura
AU - McGuire, Marianne
AU - Pietryga, Marguerite
AU - Ramsdell, Linda
AU - Slattery, Leah
AU - Abid, Farida
AU - Bertuch, Alison A.
AU - Grange, Dorothy
AU - Immken, La Donna
AU - Schaaf, Christian P.
AU - Van Esch, Hilde
AU - Bi, Weimin
AU - Cheung, Sau Wai
AU - Breman, Amy M.
AU - Smith, Janice L.
AU - Shaw, Chad
AU - Crosby, Andrew H.
AU - Eng, Christine
AU - Yang, Yaping
AU - Lupski, James R.
AU - Xiao, Rui
AU - Liu, Pengfei
N1 - Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - Atypical cohesinopathies
KW - Clinical exome sequencing (CES)
KW - Cohesin pathway
KW - STAG1
KW - STAG2
UR - http://www.scopus.com/inward/record.url?scp=85053293628&partnerID=8YFLogxK
U2 - 10.1038/s41436-018-0085-6
DO - 10.1038/s41436-018-0085-6
M3 - Article
C2 - 30158690
AN - SCOPUS:85053293628
SN - 1098-3600
VL - 21
SP - 663
EP - 675
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 3
ER -