Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
30
05
2021
accepted:
09
08
2021
pubmed:
20
8
2021
medline:
27
4
2022
entrez:
19
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34410491
doi: 10.1007/s00439-021-02336-6
pii: 10.1007/s00439-021-02336-6
pmc: PMC9035008
doi:
Substances chimiques
Membrane Transport Proteins
0
SLC26A4 protein, human
0
Sulfate Transporters
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
465-484Subventions
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek
ID : 184.034.019
Investigateurs
M F van Dooren
(MF)
S G Kant
(SG)
H H W de Gier
(HHW)
E H Hoefsloot
(EH)
M P van der Schroeff
(MP)
L J C Rotteveel
(LJC)
F G Ropers
(FG)
J C C Widdershoven
(JCC)
J R Hof
(JR)
E K Vanhoutte
(EK)
I Feenstra
(I)
H Kremer
(H)
C P Lanting
(CP)
R J E Pennings
(RJE)
H G Yntema
(HG)
R H Free
(RH)
J S Klein Wassink-Ruiter
(JSK)
R J Stokroos
(RJ)
A L Smit
(AL)
M J van den Boogaard
(MJ)
F A Ebbens
(FA)
S M Maas
(SM)
A Plomp
(A)
T P M Goderie
(TPM)
P Merkus
(P)
J van de Kamp
(J)
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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