Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.

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.

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.