AUTHOR=Huang Yu , Geng Jia , Long Yang , Xiong Wenyu , Kang Lu , Chen Meilin , Tang Ting , Zhong Mingjun , Bu Fengxiao , Lu Yu , Cheng Jing , Yuan Huijun 

TITLE=Five novel cis-regulatory deletions of SOX10 cause Waardenburg syndrome type II

JOURNAL=Frontiers in Audiology and Otology

VOLUME=2

YEAR=2024

URL=https://www.frontiersin.org/journals/audiology-and-otology/articles/10.3389/fauot.2024.1400991

DOI=10.3389/fauot.2024.1400991

ISSN=2813-6055

ABSTRACT=<sec><title>Introduction</title><p>Waardenburg syndrome (WS) is a genetic disorder characterized by hearing loss, hypopigmentation, and distinct facial features. Despite &gt; 60% molecular diagnosis rate for WS patients, pathogenic variants within coding regions are predominant, with few non-coding copy number variations (CNVs) reported.</p></sec><sec><title>Methods</title><p>In this study, we performed whole genome sequencing (WGS) on 59 undiagnosed WS patients and analyzed the CNVs within the promoter and enhancer regions of the <italic>SOX10</italic> gene.</p></sec><sec><title>Results</title><p>We identified five novel pathogenic deletions ranging from 448 bp to 70 kb upstream of <italic>SOX10</italic>. Two deletions were in the enhancer region, while three were in the promoter and 5'UTR region. These CNVs manifested as WS type II in eight patients from five unrelated families, demonstrating phenotypic heterogeneity. Furthermore, analysis of CNV1 within the enhancer region suggested a potential mechanism involving <italic>Alu</italic>-mediated non-allelic homologous recombination (NAHR).</p></sec><sec><title>Conclusion</title><p>Our findings extend the mutation spectrum of the <italic>SOX10</italic> gene and elucidate the pathogenic role of CNVs in cis-regulatory elements, particularly variations in enhancer and promoter regions, thereby enhancing clinical gene detection and interpretation of non-coding regions.</p></sec>