Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research.

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Exploring the Missing Heritability in Subjects With Hearing Loss, Enlarged Vestibular Aqueducts, and A Single or No Pathogenic SLC26A4 Variant

10.21203/rs.3.rs-577715/v1 ◽

2021 ◽

Author(s):

Jeroen Smits ◽

Suzanne E. de Bruijn ◽

Cornelis P. Lanting ◽

Jaap Oostrik ◽

Luke O’Gorman ◽

...

Keyword(s):

Hearing Loss ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Mapping ◽

Copy Number Variants ◽

Whole Genome ◽

Missing Heritability ◽

Vestibular Aqueduct ◽

Pathogenic Variants ◽

Long Read

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 SLC26A4 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, short- and long-read whole genome sequencing and optical genome mapping were performed. We found a previously described EVA-associated haplotype (Caucasian EVA (CEVA)) to be significantly enriched in our M1 patient cohort. The haplotype was also present in two M0 cases. Despite extensive genetic analyses, we were not able to prioritize any of the variants present within the haplotype as the likely pathogenic defect, and therefore additional analyses addressing the defect(s) at the RNA, protein, or epigenetic level are required. Whole genome sequencing also revealed splice-altering SLC26A4 variants in two M1 cases, which are now genetically explained, but no deep-intronic or copy number variants. With these findings, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases.

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

Human Genetics ◽

10.1007/s00439-021-02336-6 ◽

2021 ◽

Author(s):

Jeroen J. Smits ◽

Suzanne E. de Bruijn ◽

Cornelis P. Lanting ◽

Jaap Oostrik ◽

Luke O’Gorman ◽

...

Keyword(s):

Hearing Loss ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Mapping ◽

Whole Genome ◽

Missing Heritability ◽

Single Nucleotide Variants ◽

Vestibular Aqueduct ◽

Pathogenic Variants ◽

Long Read

AbstractPathogenic 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.

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