Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

Jeroen J Smits,Sjoert Pegge ,Kornelia Neveling,Susanne Roosing,Tuomo Mantere,Jaap Oostrik,Cornelis P Lanting,Frans P.m Cremers ,Helger G Yntema,Alexander Hoischen,Erik De Vrieze,Luke O’Gorman,Suzanne E De Bruijn,Ronny Derks,Ronald J.e Pennings ,Hannie Kremer

doi:10.1007/s00439-021-02336-6

Jeroen J Smits, Sjoert Pegge + Show 14 more

Open Access

https://doi.org/10.1007/s00439-021-02336-6

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Abstract

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Highlights

SLC26A4 encodes the transmembrane anion transporter pendrin and is most abundantly expressed in the inner ear, thyroid gland, kidney, and airways epithelia (Everett et al 1997, 1999; Pedemonte et al 2007; Royaux et al 2000, 2001)
Causative variants in other genes associated with autosomal recessive hearing loss (arHL) (Van Camp and Smith 2021) were addressed and excluded by analyzing available sequencing data (WES or molecular inversion probe (MIP)-based) or in wholegenome sequencing (WGS) data obtained in this study (Online Resource Table S2)
We investigated 28 genetically unexplained Dutch index cases with HL and a unilateral or bilateral enlarged vestibular aqueduct (EVA)

Summary

Introduction

SLC26A4 encodes the transmembrane anion transporter pendrin and is most abundantly expressed in the inner ear, thyroid gland, kidney, and airways epithelia (Everett et al 1997, 1999; Pedemonte et al 2007; Royaux et al 2000, 2001). The protein is expressed in the epithelial cells of the cochlea (outer sulcus and spindle cells), the vestibular labyrinth (transitional cells), and the endolymphatic duct and sac (mitochondrial-rich cells) (Wangemann 2011; Wangemann et al 2007). Expression of pendrin is essential for the development of the (murine) auditory and vestibular system and for maintaining ion homeostasis in the endolymphatic fluid and the endocochlear potential (Dou et al 2004; Everett et al 1999; Royaux et al 2003; Wangemann 2011)

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