Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA

Abstract

Objective: To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss.Methods: In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored.Results: Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals.Conclusion: The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology.

Enlarged vestibular aqueduct and Mondini Malformation: audiological, clinical, radiologic and genetic features

“…In this regard, in 2019, Mey et al demonstrated that individuals with two allele mutations of the Pendrin gene have a higher probability of having Mondini Malformation instead of isolated EVA [ 41 , 42 ]. Moreover, the same authors reported that SLC26A4 biallelic mutations were correlated with larger endolymphatic sac size [ 41 , 42 ]. Our findings confirmed the Mey et al thesis.…”

“…Furthermore, King et al in 2010, Rose et al in 2017, and Mey et al in 2019 demonstrated that patients with 2 mutated alleles showed worse thresholds and a tendency to progress faster than the patients with 1 or no mutated SLC26A4 alleles [ 22 , 41 – 43 ]. Also, an earlier onset of hearing loss in patients with biallelic mutations was described by those authors.…”

Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

“…SLC26A4 c.2168A>G is a well-known recurring pathogenic variant with null function previously demonstrated in an in vitro study 42 . Although SLC26A4 variants that cause hearing loss have AR inheritance, a number of previous studies demonstrated EVA with monoallelic SLC26A4 variants 43 , 44 . These monoallelic SLC26A4 variants are proposed to cause EVA in combination with either yet-to-be identified pathogenic variants in noncoding regulatory regions of SLC26A4, as supported by analysis of EVA-recurrence rates 43 – 45 , or regulatory genes of SLC26A4 , such as EPHA2 46 .…”

Phoniatric, Audiological, Orodental and Speech Problems in a Boy with Cardio-Facio-Cutaneous Syndrome Type 3 (CFC 3) Due to a Pathogenic Variant in MAP2K1 – Case Study

“…Sensorineural hearing loss is common in Turner, Richieri, Costa Pereira, Pendred and NSEVA syndromes. [22][23][24][25][26] Narrow nasal passages and adenoid overgrowth restricted the nasal obstruction, forcing the patient to breathe through an open mouth. Pathological breathing pathway through the open mouth may cause orthodontic disorders and malocclusions, and exacerbate the features of dry upper respiratory and laryngeal mucosa congestion.…”