Genomic Landscape of Branchio-Oto-Renal Syndrome through Whole-Genome Sequencing: A Single Rare Disease Center Experience in South Korea

• Published in: International journal of molecular sciences Vol. 25; no. 15; p. 8149
• Main Authors: Cho, Sung Ho, Jeong, Sung Ho, Choi, Won Hoon, Lee, Sang-Yeon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-08-2024
• Subjects: Adolescent; Adult; BOR/BO syndrome; Branchio-Oto-Renal Syndrome - genetics; Child; Child, Preschool; Diseases; DNA Copy Number Variations - genetics; DNA sequencing; Ears & hearing; Female; Genes; Genetic testing; Genomes; Genomics; Genomics - methods; Hearing loss; Homeodomain Proteins - genetics; Humans; Infant; Intracellular Signaling Peptides and Proteins - genetics; Male; molecular diagnosis; Mutation; Nuclear Proteins - genetics; Nucleotide sequencing; Patients; Pedigree; Phenotype; Protein Tyrosine Phosphatases - genetics; Rare diseases; Rare Diseases - genetics; Republic of Korea; South Korea; structural variations (SVs); Whole Genome Sequencing - methods; whole-genome sequencing (WGS); Republic of Korea; South Korea; BOR/BO syndrome; structural variations (SVs); whole-genome sequencing (WGS); molecular diagnosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158149

Branchio-oto-renal (BOR) and branchio-otic (BO) syndromes are characterized by anomalies affecting the ears, often accompanied by hearing loss, as well as abnormalities in the branchial arches and renal system. These syndromes exhibit a broad spectrum of phenotypes and a complex genomic landscape, with significant contributions from the
gene and the
gene family, including
and
. Due to their diverse phenotypic presentations, which can overlap with other genetic syndromes, molecular genetic confirmation is essential. As sequencing technologies advance, whole-genome sequencing (WGS) is increasingly used in rare disease diagnostics. We explored the genomic landscape of 23 unrelated Korean families with typical or atypical BOR/BO syndrome using a stepwise approach: targeted panel sequencing and exome sequencing (Step 1), multiplex ligation-dependent probe amplification (MLPA) with copy number variation screening (Step 2), and WGS (Step 3). Integrating WGS into our diagnostic pipeline detected structure variations, including cryptic inversion and complex genomic rearrangement, eventually enhancing the diagnostic yield to 91%. Our findings expand the genomic architecture of BOR/BO syndrome and highlight the need for WGS to address the genetic diagnosis of clinically heterogeneous rare diseases.