Identification of somatic mutations in monozygotic twins discordant for psychiatric disorders

Masaki Nishioka,Chihiro Kakiuchi,Tsukasa Sasaki,Fumichika Nishimura,Tadafumi Kato,Junko Ueda,Kiyoto Kasai,Miki Bundo,Kazuya Iwamoto,Akane Yoshikawa

doi:10.1038/s41537-018-0049-5

Abstract

Monozygotic twins are assumed to have identical genomes. Based on this assumption, phenotypic discordance in monozygotic twins has been previously attributed to environmental factors. However, recent genomic studies have identified characteristic somatic mutations in monozygotic twins discordant for Darier disease, Van der Woude syndrome, and Dravet syndrome. Here, we explored somatic mutations in four pairs of monozygotic twins discordant for schizophrenia or delusional disorder. We analyzed whole exome sequence data obtained from blood samples and identified seven somatic mutations in one twin pair discordant for delusional disorder. All seven of these mutations were validated by independent amplicon sequencing, and five of them were further validated by pyrosequencing. One somatic mutation in the patient with delusional disorder showed a missense variant in ABCC9 with an allele fraction of 7.32%. Although an association between the somatic mutations and phenotypic discordance could not be established conclusively in this study, our results suggest that somatic mutations in monozygotic twins may contribute to the development of psychiatric disorders, and can serve as high-priority candidates for genetic studies.

Highlights

Monozygotic (MZ) twins are assumed to have identical genomes.Based on this assumption, phenotypic discordance between MZ twins has been attributed to environmental factors
In each of the following cases, only the affected twin, not the healthy co-twin, exhibited pathogenic mutations: in ATP2A2 for Darier disease,[3] in IRF6 for Van der Woude syndrome,[4] in SCN1A for Dravet syndrome,[5] and in NF1 for neurofibromatosis type 1.6 these somatic mutations were identified in peripheral tissues, they must have been shared among various tissues and were pathogenic for the patients
We performed whole exome sequence (WES) of genomic DNA isolated from blood samples obtained from four pairs of MZ twins discordant for schizophrenia or delusional disorder, and obtained sequence data at depth of 150.5× on average (Table 1)

Summary

Introduction

Monozygotic (MZ) twins are assumed to have identical genomes. Based on this assumption, phenotypic discordance between MZ twins has been attributed to environmental factors. Several cases have been discovered where MZ twins discordant for some rare disease exhibited discordant mutations in peripheral tissue samples. In each of the following cases, only the affected twin, not the healthy co-twin, exhibited pathogenic mutations: in ATP2A2 for Darier disease,[3] in IRF6 for Van der Woude syndrome,[4] in SCN1A for Dravet syndrome,[5] and in NF1 for neurofibromatosis type 1.6 these somatic mutations were identified in peripheral tissues, they must have been shared among various tissues and were pathogenic for the patients. Not conclusive regarding the effect on the phenotype, one study that carried out exome-wide investigation detected mutations in FBXO38, SMOC2, and TDRP only in the affected twin in a pair of MZ twins discordant for gender dysphoria.[7]

Methods

Results

Conclusion