Identification of ANLN as a new likely pathogenic gene of branchio-otic syndrome in a three-generation Chinese family

Background Branchio-oto-renal (BOR) syndrome is one of the most common autosomal dominant hearing loss syndromes and features clinical and genetic heterogeneity. When there is no renal deformity, this disease can also be called branchio-otic (BO) syndrome. Though many genes have been reported, there are still many BO syndrome-related genes to be identified. To identify a hitherto unknown candidate gene causing BO syndrome in a three-generation Chinese family, clinical, genetic, and functional analyses were employed. Methods Whole-exome sequencing (WES) was conducted in three affected family members and two unaffected family members. PCR-Sanger sequencing was performed in all of the family members for segregation analysis and verification of the candidate variants. PCR-Sanger sequencing was also employed in 150 healthy people to examine the variants. In silico analysis was used to predict possible changes in the protein structure that may affect the phenotype. Results We identified a heterozygous missense variant in ANLN: NM_018685.4: c.G1105A; NP_061155.2: p.G369R that segregated in the pedigree with an autosomal dominant pattern. No variant was found in the 150 controls and normal family members at this site. The variant c.G1105A was located in a highly conserved F-actin binding site. The amino acid residue at position 369 in the ANLN protein was highly conserved across different species. Conclusion In this study, we identified, for the first time, a heterozygous missense variant in ANLN (NM_018685.4: c.G1105A; NP_061155.2: p.G369R) that is likely to be a candidate causative gene of BO syndrome in a specific Chinese family.