Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

Chakchouk, Imen; Zhang, Di; Zhang, Zhihui; Francioli, Laurent C.; Santos‐Cortez, Regie Lyn P.; Schrauwen, Isabelle; Leal, Suzanne M.

doi:10.1038/s41431-019-0417-2

Cited by 19 publications

(21 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, 120 nonsyndromic HI genes have been identified, with 59% having an autosomal recessive (AR), 37% an autosomal dominant (AD), and 5% an X-linked mode of inheritance (Hereditary hearing loss homepage). However, many genes remain to be identified due to the complexity of the hearing system and due to the understudy of some ancestries [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment

Schrauwen

Liaqat

Schatteman

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

Congenital hearing impairment is a sensory disorder that is genetically highly heterogeneous. By performing exome sequencing in two families with congenital nonsyndromic profound sensorineural hearing loss (SNHL), we identified autosomal dominantly inherited missense variants [p.(Asn283Ser); p.(Thr116Ile)] in GREB1L, a neural crest regulatory molecule. The p.(Thr116Ile) variant was also associated with bilateral cochlear aplasia and cochlear nerve aplasia upon temporal bone imaging, an ultra-rare phenotype previously seen in patients with de novo GREB1L variants. An important role of GREB1L in normal ear development has also been demonstrated by greb1l−/− zebrafish, which show an abnormal sensory epithelia innervation. Last, we performed a review of all disease-associated variation described in GREB1L, as it has also been implicated in renal, bladder and genital malformations. We show that the spectrum of features associated with GREB1L is broad, variable and with a high level of reduced penetrance, which is typically characteristic of neurocristopathies. So far, seven GREB1L variants (14%) have been associated with ear-related abnormalities. In conclusion, these results show that autosomal dominantly inherited variants in GREB1L cause profound SNHL. Furthermore, we provide an overview of the phenotypic spectrum associated with GREB1L variants and strengthen the evidence of the involvement of GREB1L in human hearing.

show abstract

Section: Introductionmentioning

confidence: 99%

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment

Schrauwen

Liaqat

Schatteman

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, variant impact predictors tend to train catalogued variants from databases, which are not representative of all ancestries. ClinVar was recently found to be missing a large number of hearing impairment variants that primarily affect individuals of African ancestry 52 , likely indicative of a broader pattern. For variant predictors, this bias will lead to greater reliance on European ancestry variants and European genetic context, producing less accurate classification of IEM and PGX variants in other ancestries (e.g., African ancestry), which would only compound existing injustice in healthcare access for underrepresented populations 53,54 .…”

Section: Ethical Considerations In Rare Variant Interpretationmentioning

confidence: 99%

Opportunities and Challenges for Interpreting Rare Variation in Clinically Important Genes

McInnes¹,

Ag²,

Ml³

et al. 2020

Preprint

View full text Add to dashboard Cite

Genome sequencing is enabling precision medicine—tailoring treatment to the unique constellation of variants in an individual’s genome. The impact of recurrent pathogenic variants is often understood, leaving a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequent frequent variants and associated mechanisms. Variants of unknown significance (VUS) in these genes are discovered at a rate that outpaces current ability to classify them using databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns, and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

show abstract

“…However, the detection rate was 70% for 10 mutiplex Cameroonian families [ 11 ]. Moreover, the prevalence of autosomal recessive non-syndromic hearing impairment (ARNSHI) pathogenic and likely pathogenic (PLP) variants, using data from the genome aggregation database (gnomAD) database [ 12 ] were estimated to account for ARNSHI in 5.2 per 100,000 individuals for Africans/African Americans, compared to 96.9 per 100,000 individuals for Ashkenazi Jews based on sequence data [ 13 ]. Therefore, there is an urgent need to investigate HI in populations of African ancestry, particularly multiplex families, using next generation sequencing, to improve knowledge a variants and genes which underlie NSHI in African populations.…”

Section: Introductionmentioning

confidence: 99%

Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

Wonkam‐Tingang

Schrauwen

Esoh

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.

show abstract

Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

Cited by 19 publications

References 39 publications

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment

Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment

Opportunities and Challenges for Interpreting Rare Variation in Clinically Important Genes

Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

Contact Info

Product

Resources

About