A Multi-omic approach to genetic hearing loss in the Newfoundland founder population

Pater, Justin (2019) A Multi-omic approach to genetic hearing loss in the Newfoundland founder population. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Hearing loss is the most common sensory disorder and despite the identification of over 143 genes, many loci remain unsolved. Therefore, the identification of novel genes are of great importance to provide insight into disease pathways and improve the diagnosis and management of hearing loss. Due to a limited gene pool, genetic isolates, such as the island of Newfoundland, provide unprecedented opportunities for gene discovery. The objective of this thesis was to identify the genetic basis of hearing loss in several large Newfoundland families with either autosomal recessive or dominant hearing loss. Firstly, we identified a pathognomonic deafness, autosomal recessive 29 (DFNB29; OMIM: 614035) phenotype that was caused by a novel pathogenic CLDN14 missense variant, which resided on a 1.4 Mb ancestral haplotype across four families. Even though DFNB29 is associated with a highly variable, congenital phenotype, we observe cases of prelingual hearing loss that progresses to a distinct audioprofile. Subsequently, we identified a linked region (13q34; LOD: 4.77) within a large autosomal dominant hearing loss family that led to the discovery of a pathogenic splicing variant in a nascent ATP11A exon, which activates a cryptic splice site 153 bp downstream of the canonical splice site. This linked region overlaps with the DFNA33 locus, and hearing loss due to ATP11A exhibits significant variable expressivity, which is consistent with the family from Germany used to map this locus. Unexpectedly, three families were found to have Usher syndrome, caused by homozygous or compound heterozygous USH2A splicing variants that cosegregated in two families that were initially ascertained as non-syndromic retinitis pigmentosa, while the remaining non-syndromic hearing loss family was positive for a novel pathogenic ADGRV1 nonsense variant. Given that these families were reassigned to an Usher syndrome diagnosis based on genetic testing, this highlights the importance of employing next-generation sequencing in the clinical setting. In summary, this thesis identified a novel autosomal dominant hearing loss gene, and reclassified four variants of unknown significance to pathogenic variants, ascertaining the genetic etiology of deafness within eight families in the Newfoundland genetic isolate. These discoveries accelerate the diagnosis and surveillance of those at-risk of developing hearing loss, as well as enrolment into promising clinical trials.

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