Genetic etiology of non-syndromic hearing loss in Latin America

Lezirovitz, Karina; Mingroni‐Netto, Regina Célia

doi:10.1007/s00439-021-02354-4

Cited by 8 publications

(16 citation statements)

References 140 publications

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“…Although the small sample, OTOF screening showed effectiveness in providing a molecular diagnosis for auditory neuropathy patients and consequently a good prognosis for a cochlear implant. In accordance, a high prevalence of OTOF causative variants was revealed in patients with AN, in a follow-up of the study conducted by Romanos et al (2009), ~ 86% (12/14), which is presented in this issue (Lezirovitz and Mingroni-Netto 2021). It is noteworthy that residue 161 is located near the surface.…”

Section: Otof and Auditory Neuropathysupporting

confidence: 67%

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss

et al. 2021

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Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.

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Section: Otof and Auditory Neuropathysupporting

confidence: 67%

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss

et al. 2021

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“…Interestingly, the same heterozygous missense variant c.1813G>A, p,(Gly605Arg) was found in another genetically undiagnosed proband with congenital bilateral severe SNHL from the Henan cohorts. In addition, the frameshift variant c.8452_8468del, p,(Leu2818TyrfsTer5) was also found in a genetically diagnosed proband (heterozygous c.8452_8468del; MYO7A c.689C>T, p.(Ala230Val), a known MYO7A pathogenic variant, ( https://www.ncbi.nlm.nih.gov/clinvar/variation/178993/ ) (Di Leva et al 2006 ; Kaneko et al 2017 ; Lezirovitz and Mingroni-Netto 2022 ) with congenital bilateral SNHL from the Henan cohorts.…”

Section: Resultsmentioning

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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“…Interestingly, the same heterozygous missense variant c.1813G>A, p,(Gly605Arg) was found in another genetically undiagnosed proband with congenital bilateral severe SNHL from the Henan cohorts. In addition, the frameshift variant c.8452_8468del, p,(Leu2818TyrfsTer5) was also found in a genetically diagnosed proband (heterozygous c.8452_8468del; MYO7A c.689C>T, p.(Ala230Val), a known MYO7A pathogenic variant, (https://www.ncbi.nlm.nih.gov/clinvar/variation/178993/) (Di Leva et al 2006; Kaneko et al 2017; Lezirovitz and Mingroni-Netto 2022) with congenital bilateral SNHL from the Henan cohorts.…”

Section: Resultsmentioning

confidence: 97%

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

Redfield,

De-la-Torre,

Zamani

et al. 2023

Preprint

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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.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.

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Genetic etiology of non-syndromic hearing loss in Latin America

Cited by 8 publications

References 140 publications

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss

Molecular and genetic characterization of a large Brazilian cohort presenting 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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