Abstract
PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.
Highlights
Usher syndrome (USH) is the leading cause of hereditary sensory deaf-blindness in humans [1]
By short tandem-repeat (STR) genotyping, we evaluated whether p.Arg164Trp is linked to a single common haplotype with a founder effect
Based on our STR marker genotyping results where we observed the p.Arg164Trp was statistically significantly associated with a certain haplotype, consisting of three hypervariable informative STR markers (D10S192, D10S1697, D10S1268) flanking PDZD7 and higher prevalence in Korean MAF population database (KRGDB) than in global population database (ExAC and Genome Aggregation Database (GnomAD) Exome) by at least one order of magnitude, we reasoned that this variant could exert a founder effect at least in Koreans
Summary
Usher syndrome (USH) is the leading cause of hereditary sensory deaf-blindness in humans [1]. USH2 is the most common type, characterized by moderate-to-severe hearing loss, preserved vestibular function, and progressive retinal photoreceptor degeneration [3]. Variants in the USH2A, ADGRV1, WHRN, and PDZD7 genes are associated with USH2 in humans [4,5,6]. PDZD7 encodes a PDZ domain-containing scaffold protein, which plays a critical role in the organization of the USH2 interactome [7]. PDZD7 was initially suggested to be a causative gene of RP, a modifier of homozygous USH2 variants, and a contributor of digenic inheritance (along with ADGRV1) to the development of USH2 [6,7,8]. The morphological and functional roles of PDZD7 in the organization of cochlear hair cells have been validated in vivo and in vitro. PDZD7 is a fundamental component of normal auditory function
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