1. Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome
- Author
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Takeshi Mizuguchi, Takuma Iwaki, Veronica Eun Hue Kim, Eriko Koshimizu, Satomi Mitsuhashi, Hiromi Aoi, Noriko Miyake, Toshifumi Suzuki, Atsushi Takata, Kohei Hamanaka, Futoshi Sekiguchi, Yoshiteru Azuma, Yuri Uchiyama, Satoru Takeda, Satoko Miyatake, Chong Ae Kim, Rachel Sayuri Honjo, Débora Romeo Bertola, Atsuo Itakura, José Ricard Ceroni, Naomichi Matsumoto, and Isabel Furquim
- Subjects
0301 basic medicine ,Male ,Cornelia de Lange Syndrome ,DNA Copy Number Variations ,Chromosomal Proteins, Non-Histone ,Cell Cycle Proteins ,030105 genetics & heredity ,SMC1A ,Genetic analysis ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,EHMT1 ,De Lange Syndrome ,Exome Sequencing ,Genetics ,medicine ,Humans ,Family ,Copy-number variation ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,Mediator Complex ,biology ,Intracellular Signaling Peptides and Proteins ,NIPBL ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,medicine.disease ,DNA-Binding Proteins ,Repressor Proteins ,030104 developmental biology ,KMT2A ,Mutation ,biology.protein ,Female ,Co-Repressor Proteins ,E1A-Associated p300 Protein ,Myeloid-Lymphoid Leukemia Protein - Abstract
Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major causes of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole-exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.
- Published
- 2019