title: Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.
abstract: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.forename: Gozde
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authors.lastname: Yesil
authors.forename: Sevcan Tug
authors.initials: ST
authors.lastname: Bozdogan
authors.forename: Tulay
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authors.lastname: Tos
authors.forename: Asuman
authors.initials: A
authors.lastname: Koparir
authors.forename: Erkan
authors.initials: E
authors.lastname: Koparir
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.forename: Huseyin
authors.initials: H
authors.lastname: Aslan
authors.forename: Ozge Ozalp
authors.initials: OO
authors.lastname: Yuregir
authors.forename: Khalid
authors.initials: K
authors.lastname: Al Rubeaan
authors.forename: Dhekra
authors.initials: D
authors.lastname: Alnaqeb
authors.forename: Muneera J
authors.initials: MJ
authors.lastname: Alshammari
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.forename: Mehmed M
authors.initials: MM
authors.lastname: Atik
authors.forename: Hatip
authors.initials: H
authors.lastname: Aydin
authors.forename: B Bilge
authors.initials: BB
authors.lastname: Geckinli
authors.forename: Mehmet
authors.initials: M
authors.lastname: Seven
authors.forename: Hakan
authors.initials: H
authors.lastname: Ulucan
authors.forename: Elif
authors.initials: E
authors.lastname: Fenercioglu
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ozen
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics; D018389:Codon, Nonsense; D003635:De Lange Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005092:Exonucleases; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; C497422:KMT2A protein, human; C487465:NIPBL protein, human; D011506:Proteins; D012097:Repressor Proteins; C492318:SMC3 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D005092:Exonucleases; C113574:Rad1 protein, human; C409470:HDAC8 protein, human; D006655:Histone Deacetylases