HOXA2Haploinsufficiency in Dominant Bilateral Microtia and Hearing Loss

Abstract

Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

The genetics of auricular development and malformation: New findings in model systems driving future directions for microtia research

“…Alasti et al (2008) first reported a missense mutation, resulting in substitution of a highly conserved Glutamine for a Lysine at position 186 of HOXA2, in a consanguineous Iranian family segregating for an autosomal-recessive form of bilateral microtia. Brown and colleagues subsequently described a family with dominantly inherited non-syndromic bilateral microtia in which they identified a nonsense mutation in HOXA2 (Brown et al, 2013). The auricular features of both families were similar, however affected individuals in the Iranian family presented with more severe microtia, abnormalities of the ear canal, profound mixed hearing impairment, as well as partial cleft palate (Alasti et al, 2008), similar to that seen in the Hoxa2 -deficient mice and confirming the clinical relevance of this model.…”

“…By definition, the pinna encompasses all external structures of the ear, including the tragus and root. Patients with mutations in the coding region of HOXA2 exhibit microtia that spares structures such as the tragus, presumed derivatives of branchial arch 1 (Alasti et al, 2008; Brown et al, 2013). We believe structures orthologous to the tragus are indeed present in the adult mouse ear (see Figure 3), although these are somewhat challenging to recognize in the prenatal period.…”

Bioinformatics analysis of microRNA comprehensive regulatory network in congenital microtia

“…Coulbault et al [9] suggested that the bone morphogenetic protein 5 maternal peptide gene acted as the predisposing genes of microtia. Additionally, homeobox A2 has previously been demonstrated to be linked to autosomal recessive bilateral microtia [2]. Importantly, Li et al [7] attempted to reveal the involvement of microRNA (miRNA) in microtia pathogenesis by screening miRNAs expression profiling of microtia and found that the abnormal expression of miR-200c, miR-451 and miR-486-5p could be possible causes of microtia.…”

“…Microtia is a congenital malformation of the external ear, characterized by a small, abnormally shaped auricle [1,2]. This disease occurs in 1 out of about 8000-10,000 births with phenotypes ranging from minor deformities to complete absence of the external ear [3].…”

Association of Klinefelter Syndrome and Congenital Auricle Dysplasia: Case Report

“…Ayrıca; MNDEC (4p16-15), FGF3 (11q13), HOXA2 (7p15,2), RPS28 (19p13,2), EYA1 (8q13,3), PRKRA (2q31,2), WNT3 (17q21), SIX2 (2p21), GSC (14q32,13), HOXA1 (7p15,2) genlerinin mikroti ile ilişkili olduğu bilinmektedir; fakat bu genlerin hiçbirinin X ve Y kromozomları ile ilişkisi bulunmamaktadır. 15 Olgumuzun ise izole auriküler malformasyonla Klinefelter sendromunun tesadüfî birlikteliği olabileceği düşünülmüştür. Bu çalışma, böyle bir birlikteliğin ilk kez görülmesi nedeniyle literatüre katkı sağlaması amacıyla sunulmuştur.…”