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

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 case...

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Vydané v:Human genetics Ročník 141; číslo 3-4; s. 465 - 484
Hlavní autori: Smits, Jeroen J., de Bruijn, Suzanne E., Lanting, Cornelis P., Oostrik, Jaap, O’Gorman, Luke, Mantere, Tuomo, Cremers, Frans P. M., Roosing, Susanne, Yntema, Helger G., de Vrieze, Erik, Derks, Ronny, Hoischen, Alexander, Pegge, Sjoert A. H., Neveling, Kornelia, Pennings, Ronald J. E., Kremer, Hannie
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2022
Springer
Springer Nature B.V
Predmet:
Biomedical and Life Sciences
Biomedicine
Deafness
DNA sequencing
Epigenetic inheritance
Epigenetics
Ethylenediaminetetraacetic acid
Gene Function
Gene mapping
Gene mutations
Genetic aspects
Genomes
Genomics
Genotypes
Haplotypes
Health aspects
Hearing loss
Hearing Loss - genetics
Hearing Loss, Sensorineural - genetics
Heritability
Human Genetics
Humans
Investigations
Membrane Transport Proteins - genetics
Metabolic Diseases
Molecular Medicine
Mutation
Nucleotide sequencing
Original Investigation
Phenotype
Phenotypes
RNA
Sulfate Transporters - genetics
The Molecular Genetics of Hearing and Deafness
Vestibular Aqueduct - abnormalities
Vestibular system
Whole genome sequencing
ISSN:0340-6717, 1432-1203, 1432-1203
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Popis
Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0340-6717
1432-1203
1432-1203
DOI:10.1007/s00439-021-02336-6