TY - JOUR
T1 - Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes
AU - Yuan, Bo
AU - Pehlivan, Davut
AU - Karaca, Ender
AU - Patel, Nisha
AU - Charng, Wu Lin
AU - Gambin, Tomasz
AU - Gonzaga-Jauregui, Claudia
AU - Sutton, V. Reid
AU - Yesil, Gozde
AU - Bozdogan, Sevcan Tug
AU - Tos, Tulay
AU - Koparir, Asuman
AU - Koparir, Erkan
AU - Beck, Christine R.
AU - Gu, Shen
AU - Aslan, Huseyin
AU - Yuregir, Ozge Ozalp
AU - Rubeaan, Khalid Al
AU - Alnaqeb, Dhekra
AU - Alshammari, Muneera J.
AU - Bayram, Yavuz
AU - Atik, Mehmed M.
AU - Aydin, Hatip
AU - Geckinli, B. Bilge
AU - Seven, Mehmet
AU - Ulucan, Hakan
AU - Fenercioglu, Elif
AU - Ozen, Mustafa
AU - Jhangiani, Shalini
AU - Muzny, Donna M.
AU - Boerwinkle, Eric
AU - Tuysuz, Beyhan
AU - Alkuraya, Fowzan S.
AU - Gibbs, Richard A.
AU - Lupski, James R.
PY - 2015/2/2
Y1 - 2015/2/2
N2 - Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
AB - Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
UR - http://www.scopus.com/inward/record.url?scp=84961290013&partnerID=8YFLogxK
U2 - 10.1172/JCI77435
DO - 10.1172/JCI77435
M3 - Article
C2 - 25574841
AN - SCOPUS:84961290013
SN - 0021-9738
VL - 125
SP - 636
EP - 651
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -