title: Numerous BAF complex genes are mutated in Coffin-Siris syndrome.
abstract: Coffin-Siris syndrome (CSS; OMIM#135900) is a rare congenital anomaly syndrome characterized by intellectual disability, coarse face, hypertrichosis, and absence/hypoplasia of the fifth digits' nails. As the majority of patients are sporadic, an autosomal dominant inheritance model has been postulated. Recently, whole exome sequencing (WES) emerged as a comprehensive analytical method for rare variants. We applied WES on five CSS patients and found two de novo mutations in SMARCB1. SMARCB1 was completely sequenced in 23 CSS patients and the mutations were found in two more patients. As SMARCB1 encodes a subunit of the BAF complex functioning as a chromatin remodeling factor, mutations in 15 other subunit genes may cause CSS and thus were analyzed in 23 CSS patients. We identified heterozygous mutations in either of six genes (SMARCA4, SMARCB1, SMARCA2, SMARCE1, ARID1A, and ARID1B) in 20 out of 23 CSS patients. The patient with a SMARCA2 mutation was re-evaluated and identified as having Nicolaides-Baraitser syndrome (OMIM#601358), which is similar to but different from CSS. Additionally, 49 more CSS patients were analyzed as a second cohort. Together with the first cohort, 37 out of 71 (22 plus 49) patients were found to have a mutation in either one of five BAF complex genes. Furthermore, two CSS patients were reported to have a PHF6 abnormality, which can also cause Borjeson-Forssman-Lehmann syndrome (OMIM#301900), an X-linked intellectual disability syndrome with epilepsy and endocrine abnormalities. The current list of mutated genes in CSS is far from being complete and analysis of more patients is required.
authors: Noriko
authors: N
authors: Miyake
authors: Yoshinori
authors: Y
authors: Tsurusaki
authors: Naomichi
authors: N
authors: Matsumoto
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D059472:Exome; D005145:Face / Q000002:abnormalities*; D019066:Facies; D005385:Fingers / Q000002:abnormalities; D005532:Foot Deformities, Congenital / Q000235:genetics; D056726:Genetic Association Studies; D006130:Growth Disorders / Q000235:genetics; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007039:Hypotrichosis / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000235:genetics; D008844:Micrognathism / Q000235:genetics*; D009154:Mutation; D059645:Mutation Rate; D009333:Neck / Q000002:abnormalities*; D009687:Nuclear Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics; D012097:Repressor Proteins; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; C497837:ARID1B protein, human; D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C502542:PHF6 protein, human; D012097:Repressor Proteins; C084011:SMARCA2 protein, human; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C504738:SMARCE1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Coffin-Siris syndrome; copy number analysis; gene identification; target resequencing; whole exome sequencing