Identification and characterization of candidate genes in individuals with autosomal recessive intellectual disability

Language
en
Document Type
Doctoral Thesis
Issue Date
2018-06-11
Issue Year
2018
Authors
Tawamie, Hasan
Editor
Abstract

By applying a combination of homozygosity mapping and whole exome sequencing I aimed in this thesis at identifying the genetic causes of intellectual disability in nineteen consanguineous families with two or more affected children. Following identification of genetic variants I prioritized them based on frequency, computer-based modeling, protein function, and familial segregation. In two families, I identified homozygous pathogenic variants in AHI1 and SPG20 that were already associated with Joubert syndrome and Troyer syndrome, respectively. In 14 families, I identified 15 candidate variants in genes not previously associated with intellectual disability, BDH1, CCAR2, EZR, FAR1, KCTD18, KIAA0586, LRCH3, OGDHL, PGAP1, PGAP2, PUS7, SKIDA1, SVBP, TAF13, and TMTC3. In three families, I could identify no candidate variants. To confirm the pathogenicity of the identified variants, working hypotheses were generated based on the putative variant effect and/or on the protein function and on results of the molecular modeling of the altered protein. For SVBP I could show severe reduction of the secretion of the interaction partner VASH1 in cells with overexpression of the altered SVBP. For TAF13 I could prove that the variant leads to major disruption of the interaction between TAF13 and TAF11. TAF13 is involved in transcription. Thus, I have also performed whole RNA sequencing on TAF13-knocked down neuron-like cell lines. This revealed that transcription of genes that are involved in proliferation and differentiation of neurons is impacted. I proved this in cell cultures. Since further analyses was not possible within this thesis, experiments to prove the pathogenicity and/or causality of the variants in EZR, FAR1, KIAA0586, PGAP1, PGAP2, and TMTC3 were done by cooperation partners, after I have performed preliminary work of validation, segregation, testing for frequency in general population, and vector construction. In conclusion, in this thesis I could identify or contribute to the identification of 8 novel genes for autosomal recessive intellectual disability.

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