Chen Robert, Diaz-Miranda Maria Alejandra, Aref-Eshghi Erfan, Hartman Tiffiney R, Griffith Christopher, Morrison Jennifer L, Wheeler Patricia G, Torti Erin, Richard Gabriele, Kenna Margaret, Dechene Elizabeth T, Spinner Nancy B, Bai Renkui, Conlin Laura K, Krantz Ian D, Amr Sami S, Luo Minjie
Department of Pathology and Laboratory Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Hum Mutat. 2022 Dec;43(12):1837-1843. doi: 10.1002/humu.24443. Epub 2022 Aug 2.
Synonymous variants have been shown to alter the correct splicing of pre-mRNAs and generate disease-causing transcripts. These variants are not an uncommon etiology of genetic disease; however, they are frequently overlooked during genetic testing in the absence of functional and clinical data. Here, we describe the occurrence of a synonymous variant [NM_005422.4 (TECTA):c.327C>T, p.(Gly109=)] in seven individuals with hearing loss from six unrelated families. The variant is not located near exonic/intronic boundaries but is predicted to impact splicing by activating a cryptic splicing donor site in exon 4 of TECTA. In vitro minigene assays show that the variant disrupts the reading frame of the canonical transcript, which is predicted to cause a premature termination codon 48 amino acids downstream of the variant, leading to nonsense-mediated decay. The variant is present in population databases, predominantly in Latinos of African ancestry, but is rare in other ethnic groups. Our findings suggest that this synonymous variant is likely pathogenic for TECTA-associated autosomal recessive hearing loss and seems to have arisen as a founder variant in this specific Latino subpopulation. This study demonstrates that synonymous variants need careful splicing assessment and support from additional testing methodologies to determine their clinical impact.
同义变异已被证明会改变前体mRNA的正确剪接，并产生致病转录本。这些变异并非罕见的遗传病病因；然而，在缺乏功能和临床数据的情况下，它们在基因检测中经常被忽视。在此，我们描述了一个同义变异[NM_005422.4 (TECTA):c.327C>T, p.(Gly109=)]在来自六个无关家庭的七名听力损失个体中的出现情况。该变异并不位于外显子/内含子边界附近，但预计会通过激活TECTA外显子4中的一个隐蔽剪接供体位点来影响剪接。体外小基因分析表明，该变异破坏了正常转录本的阅读框，预计会在变异下游48个氨基酸处产生一个过早终止密码子，导致无义介导的衰变。该变异存在于人群数据库中，主要在非洲裔拉丁裔中，但在其他种族群体中很少见。我们的研究结果表明，这种同义变异可能是与TECTA相关的常染色体隐性听力损失的致病原因，并且似乎是在这个特定的拉丁裔亚群体中作为一个奠基者变异出现的。这项研究表明，同义变异需要仔细的剪接评估以及其他检测方法的支持，以确定它们的临床影响。
