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Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.
- Source :
-
Journal of human genetics [J Hum Genet] 2021 Jun; Vol. 66 (6), pp. 597-606. Date of Electronic Publication: 2021 Jan 06. - Publication Year :
- 2021
-
Abstract
- The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM_032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.
- Subjects :
- Cloning, Molecular methods
DNA Mutational Analysis
Exome genetics
Female
Genetic Linkage
Genetic Predisposition to Disease
Haplotypes genetics
Histone Demethylases genetics
Histones genetics
Humans
Intellectual Disability epidemiology
Intellectual Disability pathology
Japan epidemiology
Male
Marfan Syndrome epidemiology
Marfan Syndrome pathology
Methylation
Mutation genetics
Pedigree
Schizophrenia epidemiology
Schizophrenia pathology
Exome Sequencing
F-Box Proteins genetics
Intellectual Disability genetics
Jumonji Domain-Containing Histone Demethylases genetics
Marfan Syndrome genetics
Schizophrenia genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1435-232X
- Volume :
- 66
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33402700
- Full Text :
- https://doi.org/10.1038/s10038-020-00889-4