Bengl Daniel, Koparir Asuman, Prastyo Wahyu Eka, Remmele Christian, Dittrich Marcus, Flandin Sophie, Shehata-Dieler Waafa, Grimm Clemens, Haaf Thomas, Hofrichter Michaela A H
Institute of Human Genetics, Julius Maximilians University, Am Hubland, Würzburg, 97074, Bavaria, Germany.
Center for Rare Diseases, University Clinics, Josef-Schneider-Straße 2, Würzburg, 97080, Bavaria, Germany.
BMC Med Genomics. 2025 Mar 31;18(1):59. doi: 10.1186/s12920-025-02122-7.
BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset.
Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families ( 43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay.
In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.
背景/目的：听力损失（HL）是最常见的先天性疾病之一，每1000名新生儿中有1至2人受其影响。使用大型基因panel和/或全外显子组分析（WES）的现代基因诊断方法可在25%至50%的患者中识别出致病突变，发病较早的个体中诊断率更高。
在此，我们使用全基因组测序（WGS）对14名通过WES仍未得到基因诊断的索引患者/家庭进行重新分析。我们能够在6个家庭（43%）中确定HL的遗传原因。两个家庭被诊断为DFNB84A，由PTPRQ中的复合杂合隐性突变引起。四个潜在变异中的三个，包括一个结构变异、一个内含子深处变异和一个剪接变异，未被WES检测到。小基因检测证实了内含子变异和剪接变异的致病性。此外，我们使用蛋白质3D结构预测和刚性配体对接来研究逃避无义介导衰变的变异的致病性。
在我们的研究中，我们在PTPRQ中发现了四个新变异，其中三个仅通过WGS检测到。据我们所知，我们在此报告了首个导致HL的致病性内含子深处PTPRQ变异。我们的结果表明，标准WES未能很好地覆盖PTPRQ的突变谱，且PTPRQ相关的听力损失可能比以前认为的更常见。WGS在HL诊断中提供了额外的信息层。
