Department of Genetics, Institute of Physiology and Pathology of Hearing, 10 M. Mochnackiego Street, 02-042, Warsaw, Poland.
Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
Hum Genet. 2022 Apr;141(3-4):445-453. doi: 10.1007/s00439-022-02443-y. Epub 2022 Mar 7.
Novel hearing loss (HL) genes are constantly being discovered, and evidence from independent studies is essential to strengthen their position as causes of hereditary HL. To address this issue, we searched our genetic data of families with autosomal dominant HL (ADHL) who had been tested with high-throughput DNA sequencing methods. For CD164, only one pathogenic variant in one family has so far been reported. For LMX1A, just two previous studies have revealed its involvement in ADHL. In this study we found two families with the same pathogenic variant in CD164 and one family with a novel variant in LMX1A (c.686C>A; p.(Ala229Asp)) that impairs its transcriptional activity. Our data show recurrence of the same CD164 variant in two HL families of different geographic origin, which strongly suggests it is a mutational hotspot. We also provide further evidence for haploinsufficiency as the pathogenic mechanism underlying LMX1A-related ADHL.
不断有新的听力损失（HL）基因被发现，独立研究的证据对于加强它们作为遗传性 HL 病因的地位至关重要。为了解决这个问题，我们搜索了我们的常染色体显性遗传性 HL（ADHL）家族的遗传数据，这些家族已经通过高通量 DNA 测序方法进行了测试。对于 CD164，迄今为止仅在一个家族中报道了一个致病性变异。对于 LMX1A，只有两项先前的研究表明它与 ADHL 有关。在这项研究中，我们发现了两个家族的 CD164 存在相同的致病性变异，一个家族的 LMX1A 存在一个新的变异（c.686C>A；p.(Ala229Asp))，这会损害其转录活性。我们的数据显示，具有相同 CD164 变异的两个 HL 家族来自不同的地理起源，这强烈表明它是一个突变热点。我们还提供了进一步的证据，证明 LMX1A 相关的 ADHL 的致病机制是杂合子不足。
