LHFPL5 – Autosomal Recessive Nonsyndromic Hearing Loss Type 67

Autosomal recessive nonsyndromic hearing loss type 67 (DFNB67) is caused by biallelic pathogenic variants in LHFPL5 (Gene Symbol) and presents as prelingual, bilateral sensorineural hearing impairment (Disease Name). Initial linkage distinguished DFNB67 from the adjacent DFNB66 locus; targeted sequencing of LHFPL5 in one Tunisian family identified a frameshift c.89dup (p.Thr31fs) in one of 129 probands screened, confirming LHFPL5 as the DFNB67 gene ([PMID:21816241]).

In two large Turkish consanguineous pedigrees, genome-wide mapping excluded other loci and revealed homozygous LHFPL5 mutations: c.649delG (p.Glu216ArgfsTer26) and c.494C>T (p.Thr165Met), each segregating with profound hearing loss; an additional Turkish family carried the recurrent c.649delG allele on a shared haplotype ([PMID:16752389]). Subsequent screening of 96 Turkish and 90 Dutch ARNSHL cases found no LHFPL5 mutations, supporting the locus’s rarity.

A 2018 study of seven Pakistani families mapped to 6p21.31 expanded the variant spectrum to include missense and splice-region defects. Four LHFPL5 variants—c.380A>G (p.Tyr127Cys), c.452G>T (p.Gly151Val), c.250del (p.Leu84_Ile113del) and a 3′-UTR splice alteration—each segregated with hearing loss, confirming allelic heterogeneity and evolutionary conservation of affected residues ([PMID:30177809]). Overall, at least 11 unrelated families and >15 affected individuals with five distinct LHFPL5 variants have been reported.

The inheritance is autosomal recessive; segregation data include homozygosity in multiple affected siblings across consanguineous kindreds. The mutational spectrum comprises loss-of-function (frameshift, splice) and deleterious missense variants.

Functional studies in the mouse TMHS (Tmhs) ortholog demonstrate that both a spontaneous cysteine-to-phenylalanine hscy missense allele and a targeted null allele produce identical deafness and vestibular phenotypes, confirming loss-of-function as the mechanism; cochlear hair cell expression peaks perinatally ([PMID:17876667]). Further, single-molecule pulldown assays reveal that LHFPL5 physically interacts with and stabilizes TMC1 in hair cells, and human TMC1 D572N disrupts this binding, elucidating the mechanotransduction complex’s architecture ([PMID:33168709]).

No studies have disputed the biallelic loss-of-function model in DFNB67; no alternative phenotypes have been robustly associated with LHFPL5. The aggregated genetic and functional data meet criteria for a Definitive gene–disease association.

Key Take-home: Biallelic LHFPL5 variants cause DFNB67 via loss of function, and genetic testing reliably informs diagnosis of autosomal recessive nonsyndromic hearing loss.

References

• European journal of medical genetics • 2011 • DFNB66 and DFNB67 loci are non allelic and rarely contribute to autosomal recessive nonsyndromic hearing loss. [PMID:21816241]
• Human Mutation • 2006 • Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. [PMID:16752389]
• Mammalian genome : official journal of the International Mammalian Genome Society • 2007 • Targeted knockout and lacZ reporter expression of the mouse Tmhs deafness gene and characterization of the hscy-2J mutation. [PMID:17876667]
• Journal of human genetics • 2018 • Novel missense and 3′-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment. [PMID:30177809]
• Proceedings of the National Academy of Sciences of the United States of America • 2020 • Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. [PMID:33168709]

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