MYO7A – Autosomal Recessive Nonsyndromic Hearing Loss 2

MYO7A encodes the unconventional myosin VIIA motor protein, which is essential for mechanotransduction in cochlear hair cells. Biallelic variants in MYO7A are a well-established cause of Usher syndrome type 1B (USH1B), but increasing evidence supports a distinct nonsyndromic autosomal recessive hearing loss phenotype (DFNB2; [MONDO:0010807]) linked to hypomorphic or splice-affecting alleles. Clinically, DFNB2 presents as prelingual, non-syndromic sensorineural hearing loss without vestibular or retinal involvement.

Genetic studies have identified pathogenic MYO7A variants in three unrelated DFNB2 families. A Chinese pedigree harbored a maternally inherited synonymous variant c.2904G>A (p.Glu968=) and a paternally inherited missense variant c.5994G>T (p.Trp1998Cys) in the proband ([PMID:36164746]). Two Moroccan families exhibited compound heterozygous mutations (c.4487C>A (p.Thr1496Lys), c.5617C>T (p.Arg1873Trp), c.3500T>A (p.Leu1167His), c.6229T>A (p.Trp2077Arg), c.6025delG (p.Ala2009ProfsTer?)) in affected siblings ([PMID:28472130]). Together, three probands and four affected siblings support autosomal recessive inheritance with segregation of variants in trans.

The variant spectrum in DFNB2 includes missense substitutions within the motor and tail domains, truncating frameshifts, and splice-disrupting synonymous changes. No recurrent or founder alleles have been reported to date in isolated DFNB2 cohorts; carrier frequencies are unknown. All reported variants are rare or absent in population databases and are predicted to impair MYO7A function via distinct mechanisms.

Functional characterization of the synonymous c.2904G>A (p.Glu968=) variant using a minigene splicing assay demonstrated exon 23 skipping and production of a truncated transcript lacking critical IQ motifs, confirming its pathogenicity in DFNB2 ([PMID:36164746]). In silico modeling of Moroccan missense variants predicted destabilization of the motor domain and disruption of actin binding. These experimental and computational data corroborate a loss-of-function mechanism.

No conflicting evidence has been reported for MYO7A‐related DFNB2. The absence of vestibular or retinal phenotypes in DFNB2 cases distinguishes this entity from USH1B. Additional studies—including auditory cell models and mouse knock-in lines—could further elucidate genotype–phenotype correlations and inform variant classification.

In summary, biallelic MYO7A variants cause autosomal recessive nonsyndromic hearing loss type 2 (DFNB2) via hypomorphic or splice-defective mechanisms. Genetic testing for MYO7A should be considered in patients with isolated prelingual sensorineural hearing loss.

Key Take-home: MYO7A sequencing including synonymous and splice site regions enables accurate diagnosis of DFNB2, guiding genetic counseling and early intervention.

References

• PloS One • 2017 • Novel compound heterozygous MYO7A mutations in Moroccan families with autosomal recessive non-syndromic hearing loss. PMID:28472130
• Journal of Clinical Laboratory Analysis • 2022 • Novel compound heterozygous synonymous and missense variants in the MYO7A gene identified by next-generation sequencing in a Chinese family with nonsyndromic hearing loss. PMID:36164746

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