Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss

Lewis, Morag A.; Schulte, Jennifer; Matthews, Lois J.; Vaden, Kenneth I.; Steves, Claire J.; Williams, Frances; Schulte, Bradley A.; Dubno, Judy R.; Steel, Karen P.

doi:10.1101/2023.04.27.23289040

Cited by 2 publications

(2 citation statements)

References 80 publications

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“…While we have identified individuals in four families with variants in PKHD1L1, this study highlights the necessity for an extended case series with longitudinal audiological follow-up and functional studies to assess variant effects of patient-specific perturbations on development, maturation, and function of the auditory system, as well as explore the potential of accelerated effects of age, noise, or trauma on progression of hearing loss, which remain as current major limitations. Interestingly, the PKHD1L1 gene has been suggested to be associated with adult-onset hearing loss (Lewis et al 2023). Since the studied variants are also located in different residue positions in the PKHD1L1 protein sequence, the broad range of hearing impairment from these patients might suggest that these variants differentially impact the We also investigated the conservation of the mutated residue positions throughout evolution.…”

Section: Discussionmentioning

confidence: 99%

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

Redfield,

De-la-Torre,

Zamani

et al. 2024

Hum. Genet.

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Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild–moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild–moderate hearing loss may identify further affected families.

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Section: Discussionmentioning

confidence: 99%

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

Redfield,

De-la-Torre,

Zamani

et al. 2024

Hum. Genet.

View full text Add to dashboard Cite

show abstract

“…While we have identified individuals in four families with variants in PKHD1L1 , this study highlights the necessity for an extended case series with longitudinal audiological follow up and functional studies to assess variant effects of patient-specific perturbations on development, maturation, and function of the auditory system, as well as explore the potential of accelerated effects of age, noise, or trauma on progression of hearing loss, which remain as current major limitations. Interestingly, the PKHD1L1 gene has been suggested to be associated with adult-onset hearing loss (Lewis et al 2023). Since the studied variants are also located in different residue positions in the PKHD1L1 protein sequence, the broad range of hearing impairment from these patients might suggest that these variants differentially impact the protein expression, folding, and/or the stability and function of PKHD1L1.…”

Section: Discussionmentioning

confidence: 99%

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

Redfield,

De-la-Torre,

Zamani

et al. 2023

Preprint

View full text Add to dashboard Cite

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor, given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing.PKHD1L1was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants inPKHD1L1also cause hearing loss in humans.Exome sequencing was performed on DNA of three families segregating autosomal recessive moderate to severe nonsyndromic sensorineural hearing loss. Compound heterozygous missense p.[(Gly129Ser)];p.[(Gly1314Val)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified inPKHD1L1that were predicted to be damaging usingin silicopathogenicity prediction methods.In vitrofunctional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families.In vitrofunctional assessment indicated that both engineered PKHD1L1 mutant p.(Gly129Ser) and p.(Gly1314Val) constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants.In silicomolecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on protein folding and stability and exposed key structural features that might suggest PKHD1L1 protein destabilization.Multiple lines of evidence collectively associatePKHD1L1with nonsyndromic mild-moderate to severe sensorineural hearing loss.PKHD1L1testing in individuals with mild-moderate hearing loss may identify further affected families.

show abstract

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss

Cited by 2 publications

References 80 publications

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

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