Genetic investigation of Mendelian disorders in the founder populations of Newfoundland & Labrador

Evans, Daniel R. (2019) Genetic investigation of Mendelian disorders in the founder populations of Newfoundland & Labrador. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Exploring the genetic basis of monogenic disorders imparts fundamental insights into human molecular biology. Moreover, cataloguing and describing pathogenic mutations offers new genetic tests to diagnose and identify mutation carriers worldwide. Sometimes, reaching a genetic diagnosis provides long sought-after answers for patients and their families. Likewise, comprehending the genetic and clinical spectrum of rare disorders aids clinicians in managing their patients. Further, clinical knowledge obtained from genetic studies allows clinicians to anticipate and screen for potential complications. Founder populations experience higher burdens of certain Mendelian disorders and thereby provide unique circumstances to conduct genetic studies. Several founder populations exist in the Canadian province of Newfoundland & Labrador. These have proven instrumental for genetic discoveries. My thesis investigated the genetic basis of three Mendelian disorders in families from Newfoundland. These disorders include retinitis pigmentosa, Weill-Marchesani Syndrome and hereditary colorectal cancer. First, whole exome sequencing and linkage analyses were employed to investigate retinitis pigmentosa in a large kindred living on the Great Northern Peninsula of Newfoundland. This identified a linked region on chromosome 2 (logarithm of the odds 4.89 [θ = 0]) encompassing a novel pathogenic 25 kb deletion (c.845-1450del; p.Ala282_His483del) in MERTK, which segregated in the family. The molecular features and clinical manifestations of the deletion were characterized and study findings were explained to family members. Next, Weill-Marchesani Syndrome was investigated in a Newfoundland family using whole exome sequencing and homozygosity mapping. This identified a novel homozygous pathogenic missense variant (c.3068G>A, p.C1023Y) in ADAMTS17. Transfection of ADAMTS17 p.C1023Y expression plasmids into HEK293T cells revealed significantly reduced secretion of ADAMTS17 into the extracellular matrix. The clinical and molecular consequences of the variant were characterized and the family members were counselled. Finally, candidate gene screening of GALNT12 in a cohort of 479 colorectal cancer cases from Newfoundland identified eight rare variants (p.Asp303Asp; p.Arg297Trp; p.His101Gln; p.Ile142Thr; p.Glu239Gln; p.Thr286Met; p.Val290Phe; c.732-8G>T), which were overrepresented in cases compared to controls (N=400) (P=0.0381). Six of eight variants showed reduced GALNT12 enzyme activity, providing supportive evidence of a role for this gene in colorectal cancer. In summary, each study above imparted novel insights into genetic disorders in Newfoundland.

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