Pendred Syndrome, or Not Pendred Syndrome? That Is the Question.

Paola Tesolin,Claudio Granata,Veronica Castro,Anna Morgan,Giorgia Girotto,Elisa Rubinato,Elisabetta Cattaruzzi,Daniele Dell’Orco,Sofia Fiorino,Eva Orzan,Lydie Ammar,Stefania Lenarduzzi

doi:10.3390/genes12101569

Paola Tesolin, Claudio Granata + Show 10 more

Open Access

https://doi.org/10.3390/genes12101569

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Abstract

Pendred syndrome (PDS) is the most common form of syndromic Hearing Loss (HL), characterized by sensorineural HL, inner ear malformations, and goiter, with or without hypothyroidism. SLC26A4 is the major gene involved, even though ~50% of the patients carry only one pathogenic mutation. This study aims to define the molecular diagnosis for a cohort of 24 suspected-PDS patients characterized by a deep radiological and audiological evaluation. Whole-Exome Sequencing (WES), the analysis of twelve variants upstream of SLC26A4, constituting the “CEVA haplotype” and Multiplex Ligation Probe Amplification (MLPA) searching for deletions/duplications in SLC26A4 gene have been carried out. In five patients (20.8%) homozygous/compound heterozygous SLC26A4 mutations, or pathogenic mutation in trans with the CEVA haplotype have been identified, while five subjects (20.8%) resulted heterozygous for a single variant. In silico protein modeling supported the pathogenicity of the detected variants, suggesting an effect on the protein stabilization/function. Interestingly, we identified a genotype-phenotype correlation among those patients carrying SLC26A4 mutations, whose audiograms presented a characteristic slope at the medium and high frequencies, providing new insights into PDS. Finally, an interesting homozygous variant in MYO5C has been identified in one patient negative to SLC26A4 gene, suggesting the identification of a new HL candidate gene.

Highlights

Hearing loss (HL) is the most common sensory disorder affecting about 1–3 children in over 1000 [1,2,3]
HL is generally classified in non-syndromic HL (NSHL), affecting at least 70% of the patients, and syndromic HL (SHL), when other organs abnormalities are present alongside the HL [2]
Pendred syndrome (PDS) is inherited with an autosomal recessive pattern and it is associated with sensorineural HL, inner ear malformations, goitre, abnormal organification of iodide, which can cause hypothyroidism in some subjects, and vestibular dysfunction

Summary

Introduction

Hearing loss (HL) is the most common sensory disorder affecting about 1–3 children in over 1000 [1,2,3]. The most prevalent causes of HL are genetic defects that impair the production of protein with essential roles in the hearing pathway. Over 400 syndromes associated with HL have been described [4,5], suggesting the high degree of phenotypic and genetic heterogeneity that characterized the affected patients. Pendred syndrome (PDS) is considered the most common form of SHL accounting for ~4–10% of all cases of hereditary deafness [6,7]. PDS is inherited with an autosomal recessive pattern and it is associated with sensorineural HL, inner ear malformations, goitre, abnormal organification of iodide, which can cause hypothyroidism in some subjects, and vestibular dysfunction

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