Kaiyrzhanov, Rauan; (2023) Defining the Genetic Causes of Rare Paediatric Neurological Diseases in Central Asian and Transcaucasian Populations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Significant advancements in genomic medicine, made in the recent two decades, provided a molecular diagnosis for many families with rare diseases, including rare paediatric neurological diseases (RPND), increasing access to precision medicine. However, despite these advancements and the progressively decreasing cost of next-generation sequencing (NGS), many world regions remain underrepresented in human genetic research, lacking access to NGS. One of these regions is Central Asia and Transcaucasia (CAT), populated by genetically unique ethnic groups residing in the middle of Eurasia. Little is known about the genetic causes of RPND in CAT. In this work, I establish an unprecedented large-scale genetic study of RPND in CAT by interrogating a network building between University College London (UCL) and CAT, extensive patient recruitment, whole exome sequencing, and functional genomics techniques. This project was integrated into the Synaptopathies and Paroxysmal Syndromes (SYNaPS) study that had been taking place at the Institute of Neurology, UCL. Local institutional review board approvals were obtained from all participating CAT centers. Over the 3.5 years of my project, 2200 families with RPND from CAT have been recruited, and in this thesis, I report WES data, currently available from 487 families. Definitive and likely genetic diagnoses have been made for 37% and 10% of the CAT families, respectively. Firm and putative candidate novel disease-genes were found in 11%. Three of the firm novel disease-genes are reported in 3 separate chapters of this thesis (LETM1, SPATA5L1, and ACBD6) that reveal 3 novel disease pathways pertaining to mitochondrial volume homeostasis, ribosomal biogenesis, and protein posttranslational modification. Multiple international families were identified for these novel disease-genes, and deep phenotyping with extensive functional characterization is provided in the thesis. Notably, a potential mechanistic treatment is suggested for 2 of the novel disease-genes. In addition, the thesis delineates the phenotypes of the 2 known disease genes including NFU1 and EMC10. Overall, this PhD project has multiple immediate, incremental, and long-term impacts on several domains of academia as well as healthcare on both the regional and international levels, as has been explicated in the following impact statement.

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