SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management.

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• The SLC26A4 gene is a frequent cause of autosomal recessive non-syndromic sensorineural hearing loss (SNHL).
• Mutations in SLC26A4 are associated with Pendred Syndrome (PDS) and deafness with enlarged vestibular aqueduct (DFNB4), but the genotype-phenotype correlation is not always definitive.
• Phenotypic variability and intrafamilial differences in SLC26A4-related hearing loss necessitate further investigation.

Purpose of the Study:

• To investigate the molecular basis of congenital bilateral hearing loss in three Jordanian families.
• To identify novel disease-causing variants in the SLC26A4 gene.
• To correlate SLC26A4 genotypes with clinical phenotypes, including syndromic forms of hearing loss.

Main Methods:

• Whole-exome sequencing and Sanger sequencing were employed to identify genetic variants.
• Clinical evaluations included thyroid function tests, temporal bone CT scans, and thyroid ultrasounds.
• Detailed family history and clinical assessments were conducted for affected individuals.

Main Results:

• Three pathogenic variants in SLC26A4 were identified across three families, with two variants being novel.
• Two families harbored a novel homozygous splice-site variant (c.165-1G>C).
• The third family presented with compound heterozygous variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg), leading to diagnoses of typical PDS, DFNB4, and atypical PDS.

Conclusions:

• The study identified novel SLC26A4 variants contributing to hearing loss in Jordanian families.
• Genetic analysis facilitated the reclassification of non-syndromic hearing loss to syndromic forms (PDS, DFNB4).
• Findings underscore the significant intra- and inter-familial phenotypic variability associated with SLC26A4 mutations, impacting personalized healthcare management.