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. 2024 Jul 26;25(15):8149.
doi: 10.3390/ijms25158149.

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

Sung Ho Cho  1 , Sung Ho Jeong  1 , Won Hoon Choi  1 , Sang-Yeon Lee  1   2   3
Affiliations

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

Sung Ho Cho et al. Int J Mol Sci. .

Abstract

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 EYA1 gene and the SIX gene family, including SIX1 and SIX5. 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.

Keywords: BOR/BO syndrome; molecular diagnosis; structural variations (SVs); whole-genome sequencing (WGS).

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Conflict of interest statement

There are no conflicts of interest, financial or otherwise.

Figures

Figure 1
Figure 1
Cumulative molecular diagnostic yield of stepwise genomic pipeline. Targeted panel sequencing and exome sequencing were initially utilized to identify causative variants (Step 1). For patients who remained undiagnosed after targeted panel sequencing and exome sequencing, exome sequencing-based CNV screening coupled with MLPA (Step 2) was applied. Finally, WGS (Step 3) was applied to patients who remained genetically undiagnosed after Step 2.
Figure 2
Figure 2
SVs landscape of BOR/BO syndrome from literature review of BOR/BO syndrome cohort studies and this study. SVs accounted for 8.7% of all mutations reported in the cohort studies. Most of the SVs are deletions of EYA1 (89% of SVs), while complex genomic rearrangement (4% of SVs) and inversion of EYA1 (4% of SVs) are reported in a small proportion of total SVs.
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