De novo point mutations and copy number variants in discordant monozygotic twins reveals disease-susceptibility genes

Monozygotic (MZ) twins were long thought to be genetically identical, however recent studies have demonstrated genetic differences between them. To test the hypothesis that early posttwinning mutational events leads to phenotypic discordance, we investigated a cohort of eleven twin pairs discordant for a variety of clinical phenotypes and two concordant twin pairs. Whole-exome sequencing (WES) data was analysed using a union of VarScan2 and MuTect2 variant calling algorithms. Copy-number variation (CNV) analysis from Illumina HumanCore array data was also carried out using PennCNV and cnvPartition, and corroborated by computational validation with ExomeDepth. Five discordant variants were validated with Sanger sequencing, four of which were in the unaffected twin of an ALS-discordant pair ( TMEM225B, KBTBD3, TUBGCP4, TFIP11 ), and one in the affected twin with lactase non-persistence ( PLCB1). Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of germline de novo mutations with susceptibility to disease. We identified a novel de novo mutation in RASD2 shared by 8-year-old male twins concordant for a suspected diagnosis of autism sp ectrum disorder (ASD). RASD2 is enriched in the striatum and involved in the modulation of dopaminergic transmission. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene implicated in social amnesia and ASD. In twins discordant for Tourette’s syndrome, an inherited stop loss mutation was detected in AADAC, a known candidate gene for the disorder. Moreover, a rare hemizygous deletion in region 15q13.2 was detected in twins with schizophrenia, overlapping ARHGAP11B, a human-specific gene involved in basal progenitor amplification and neocortex expansion. We provide evidence for de novo point mutations and CNVs in disease-related genes associated with a variety of clinical phenotypes present in MZ twins. We also found potentially pathogenic mutations shared by discordant twins, suggesting additional genetic mechanisms, including mutations in modifier genes and epigenetic changes, might also play a role in the phenotypes.