Vadgama, Nirmal; (2017) Investigating postzygotic de novo mutations and somatic mosaicism in monozygotic twins discordant for complex disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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 post-twinning mutational events leads to phenotypic discordance, thirteen MZ twins discordant for a range of complex disorders were investigated at the genomic and proteomic level. Whole-exome sequencing 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 to identify structural variants that would not be detected by exome sequencing. All single nucleotide variants (SNVs), indels and CNVs were evaluated for functional consequence, evolutionary conservation, population frequency and overlap with known disease-susceptibility genes. Twenty-two putative discordant SNVs and indels, but no discordant structural variants, were identified. Parent-offspring trio analysis was implemented to assess potential association of germline de novo mutations with susceptibility to disease. A rare, highly conserved de novo mutation in RASD2 was detected in twins discordant for attention deficit hyperactivity disorder (ADHD). RASD2 is enriched in the striatum and involved in the modulation of dopaminergic transmission. In the twins discordant for Tourette’s syndrome, an inherited stop loss mutation was detected in AADAC, a known candidate gene for the disorder. Further, a de novo CNV duplication was identified in a twin pair discordant for ADHD overlapping CD38, a gene implicated in social amnesia and autism. When analysing the burden of shared CNVs among the twins, 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. To investigate potential downstream consequences of (epi)genetic mechanisms and underlying biochemical pathways, proteomic profiling of serum samples obtained from an MZ twin pair discordant for ischaemic stroke was analysed through a label-free pipeline. Biological processes overrepresented in the affected twin predominantly corresponded to stroke-related processes, including wound healing, blood coagulation and haemostasis. Further, a comparison of blood chemistries showed a >10- and >18-fold elevation of γ-glutamyltransferase (GGT) and erythrocyte sedimentation rate (ESR) levels respectively in the affected twin.

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