AUTHOR=Wang Rongrong , Liu Jiawei , Yang Xueting , Habulieti Xiaerbati , Yu Xue , Sun Liwei , Zhang Han , Sun Yang , Ma Donglai , Zhang Xue 

TITLE=Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.712275

DOI=10.3389/fgene.2021.712275

ISSN=1664-8021

ABSTRACT=<p><bold>Background</bold>: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in <italic>TMC6</italic>, <italic>TMC8</italic>, and <italic>CIB1</italic>. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.</p><p><bold>Methods</bold>: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant <italic>TMC6</italic> and <italic>TMC8</italic>.</p><p><bold>Results</bold>: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A &gt; G in <italic>TMC6</italic> and c.559G &gt; A in <italic>TMC8</italic>) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G &gt; A and c.1389G &gt; A, in <italic>TMC8</italic>. The c.2278-2A &gt; G <italic>TMC6</italic> variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the <italic>TMC8</italic> c.559G &gt; A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded <italic>via</italic> nonsense-mediated mRNA decay (NMD).</p><p><bold>Conclusion</bold>: We identified three novel disease-causing variants in <italic>TMC6</italic> or <italic>TMC8</italic> in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.</p>