1. An investigation into monogenic causes of male infertility
- Author
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Cheers, Samuel Robert and Cheers, Samuel Robert
- Abstract
Infertility affects 7% of men in developed societies, and the aetiology of approximately 70% of cases remains unexplained. Genetics plays a role in severe forms of male infertility, however, using current clinical approaches, it only explains 4% of cases. The overarching objective of this thesis was to identify novel genetic causes of male infertility. The work carried out here can be split into two branches – the first is an unbiased method of gene discovery using exome sequencing data from infertile men, and the second is a gene-targeted approach conducted using model organisms. In the first approach, I performed exome sequencing in 186 men with low sperm counts and their fertile parents. Potentially pathogenic variants were identified by filtering for rare variants (gnomAD AF < 0.01) classified as pathogenic or unclear by the guidelines of the American College of Medical Genetics. Genes affected by these variants were prioritized according to their likely role in male fertility. A replication analysis of candidate genes was performed in a cohort of infertile men (n=1,580) and fertile men (n=5,784). I identified 50 potential pathogenic variants (20 homozygous, 30 compound heterozygous) affecting 49 protein-encoding genes with a potential role in male fertility. Our replication analysis revealed a significant enrichment of likely pathogenic homozygous mutations in 5 of these 49 genes (AATF, FKBP6, M1AP, TEX14, and TOPAZ1, burden test p<0.05) in infertile compared to fertile men. In the second approach, model organisms were used to test and characterise the role of microtubule-associated proteins in male fertility. Microtubules are an essential component of eukaryotic cells that during spermatogenesis are required for multiple processes including cell division, sperm head shaping, and tail formation. Microtubules are regulated via microtubule-associated proteins, and while the function of many of these proteins in spermatogenesis remains poorly understood, mutations
- Published
- 2022