HOXA2 – Non-syndromic Microtia

HOXA2 variants have been implicated in both autosomal dominant and recessive forms of non-syndromic microtia, often accompanied by hearing impairment. In heterozygous families, microtia segregates in a five-generation pedigree and a three-generation pedigree as an autosomal dominant trait, while biallelic loss-of-function variants underlie an autosomal recessive form with cleft palate and profound hearing loss. Ear malformations range from mild hypoplasia to complete absence of the auricle, reflecting dosage sensitivity of HOXA2 during outer and middle ear development.

Genetic evidence includes four unrelated families: a five-generation kindred with c.670G>T (p.Glu224Ter) segregating in all affected members (PMID:27503514), a three-generation family with c.703C>T (p.Gln235Ter) (PMID:23775976), and two Chinese families harboring c.637A>T (p.Lys213Ter) and recurrence of c.703C>T in dominant bilateral microtia (PMID:32649979). Overall, 12 additional affected relatives demonstrate segregation of truncating HOXA2 alleles in dominant pedigrees.

The variant spectrum comprises three nonsense changes—c.670G>T (p.Glu224Ter), c.703C>T (p.Gln235Ter), and c.637A>T (p.Lys213Ter)—all predicted to truncate the homeodomain and absent from population databases. Biallelic missense and homeodomain variants (e.g., c.556C>A (p.Gln186Lys)) cause autosomal recessive microtia with palate anomalies, supporting a loss-of-function mechanism.

Functional studies support haploinsufficiency: a homology model of p.Gln186Lys predicts disruption of DNA-binding contacts in the homeodomain (PMID:18394579), and dual-luciferase assays show impaired activation of the HMX1 long-range enhancer by truncating alleles (PMID:32649979). Mouse models further confirm a critical requirement for Hoxa2 in ear morphogenesis.

Conflicting evidence arises from sequencing screens in sporadic microtia cohorts, where no coding HOXA2 mutations were found and only common intronic and UTR variants were detected in Hispanic, African American, and Chinese populations (PMID:20542577; PMID:28109504). These data suggest genetic heterogeneity and point to undiscovered loci in sporadic cases.

Integration of robust segregation in multiple pedigrees, a consistent truncating variant spectrum, and concordant functional assays establishes a strong gene-disease relationship for HOXA2-related microtia through haploinsufficiency. HOXA2 testing should be considered in familial non-syndromic microtia and targeted panels for congenital ear malformations.

References

• Clinical genetics • 2017 • Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non‐syndromic microtia and distinctive ear morphology PMID:27503514
• Human mutation • 2013 • HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss PMID:23775976
• Gene • 2020 • Identification of loss‐of‐function HOXA2 mutations in Chinese families with dominant bilateral microtia PMID:32649979
• American journal of human genetics • 2008 • A mutation in HOXA2 is responsible for autosomal‐recessive microtia in an Iranian family PMID:18394579
• International journal of pediatric otorhinolaryngology • 2010 • Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia PMID:20542577
• International journal of pediatric otorhinolaryngology • 2017 • Mutational analysis of GSC, HOXA2 and PRKRA in 106 Chinese patients with microtia PMID:28109504

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