title: HOXA2 haploinsufficiency 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Kerry K
authors.initials: KK
authors.lastname: Brown
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Viana
authors.forename: Cecilia C
authors.initials: CC
authors.lastname: Helwig
authors.forename: Maria A
authors.initials: MA
authors.lastname: Artunduaga
authors.forename: Lourdes
authors.initials: L
authors.lastname: Quintanilla-Dieck
authors.forename: Patricia
authors.initials: P
authors.lastname: Jarrin
authors.forename: Gabriel
authors.initials: G
authors.lastname: Osorno
authors.forename: Barbara
authors.initials: B
authors.lastname: McDonough
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.forename: Roland D
authors.initials: RD
authors.lastname: Eavey
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000013:Congenital Abnormalities / Q000235:genetics*; D065817:Congenital Microtia; D004423:Ear / Q000002:abnormalities*; D004431:Ear, External / Q000002:abnormalities; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D057895:Haploinsufficiency; D034381:Hearing Loss / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype
chemical_list: C520321:HOXA2 protein, human; D018398:Homeodomain Proteins
keywords: HOXA2; exome sequencing; hearing loss; microtia