Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul 04401, Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Korea.
Int J Mol Sci. 2019 Aug 26;20(17):4174. doi: 10.3390/ijms20174174.
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 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 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, 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.
PDZD7 是一种含有 PDZ 结构域的支架蛋白，对于 2 型 Usher 综合征（USH2）相互作用组的组织至关重要。最近，双等位基因 PDZD7 变体与常染色体隐性、非综合征性听力损失（ARNSHL）有关。事实上，我们根据美国医学遗传学与基因组学学院/分子病理学协会（ACMG/AMP）指南，从表现出疑似中度至重度语前 ARNSHL 的韩国家族中鉴定出了新的、可能具有致病性的变体；这些变体包括 c.490C>T（p.Arg164Trp）、c.1669delC（p.Arg557Glyfs*13）和 c.1526G>A（p.Gly509Glu），其中 p.Arg164Trp 是主要的复发性变体。鉴于我们队列中的反复出现的错义变体（p.Arg164Trp），我们比较了携带 p.Arg164Trp 的四个先证者和 81 名听力正常对照者的六个短串联重复（STR）标记物或其侧翼的基因分型数据。我们观察到六个 STR 基因分型标记物中的三个具有相同的单倍型，这三个标记物仅由两个无关的听力受损先证者共同拥有，但 81 名听力正常对照者中没有任何一个拥有，提示存在潜在的起源效应。然而，基于六个 STR 标记物的 STR 基因分型显示，所有受影响的受试者都共享了各种与 p.Arg164Trp 相关的单倍型。总之，在韩国人中， 可能是中度至重度 ARNSHL 的一个重要致病基因。此外，韩国人中的至少一些（如果不是全部）p.Arg164Trp 等位基因可能具有潜在的起源效应，并作为突变热点来自不同的单倍型。
