PloS one, 2017-08, Vol.12 (8), p.e0181791-e0181791
2017
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- Autor(en) / Beteiligte
- Titel
- Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH)
- Ist Teil von
- PloS one, 2017-08, Vol.12 (8), p.e0181791-e0181791
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0181791Titel-ID: cdi_plos_journals_1926896379
- Format
- –
- Schlagworte
- Aberration, Adolescent, Animals, Biology and Life Sciences, Brain research, CASK gene, Cerebellum, Cerebellum - abnormalities, Child, Child, Preschool, Chromosomes, Cytogenetics, Cytoplasmic Dyneins - genetics, Developmental Disabilities - etiology, Developmental Disabilities - genetics, Dynactin Complex - genetics, Etiology, Etiology (Medicine), Exome sequencing, Female, Females, Gene mutation, Gene sequencing, Genes, Genetic disorders, Genetic Predisposition to Disease - genetics, Genomes, Guanylate Kinases - genetics, HDAC2 protein, Histone deacetylase, Histone Deacetylase 2 - genetics, Humans, Hypoplasia, Infant, Inositol 1,4,5-Trisphosphate Receptors - genetics, Intellectual disabilities, Intellectual Disability - etiology, Intellectual Disability - genetics, Intracellular Signaling Peptides and Proteins - genetics, Kinases, Low density lipoprotein receptors, Male, MARCKS protein, Medical research, Medicine and Health Sciences, Membrane Proteins - genetics, Microcephaly, Microcephaly - etiology, Microcephaly - genetics, Microencephaly, Mutation, Mutation - genetics, Myristoylated Alanine-Rich C Kinase Substrate, Nervous system, Nervous System Malformations - etiology, Nervous System Malformations - genetics, Neurosciences, NMR, Nuclear magnetic resonance, Pathogenicity, Pathogens, Patients, Pediatrics, Point Mutation - genetics, Research and Analysis Methods, Screening, Sex differences, Single-nucleotide polymorphism, Swine, Synaptogenesis, Transfer RNA, Uncertainty analysis