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: Kerry K Brown, Lucas M Viana, Cecilia C Helwig, Maria A Artunduaga, Lourdes Quintanilla-Dieck, Patricia Jarrin, Gabriel Osorno, Barbara McDonough, Steven R DePalma, Roland D Eavey, Jonathan G Seidman, Christine E Seidman
• Journal: Human mutation (Hum Mutat) Vol. 34 Issue 10 Pg. 1347-51 (Oct 2013) ISSN: 1098-1004 [Electronic] United States
• PMID: 23775976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 WILEY PERIODICALS, INC.

Chemical References

• HOXA2 protein, human
• Homeodomain Proteins

Topics

• Congenital Abnormalities (genetics)
• Congenital Microtia
• Ear (abnormalities)
• Ear, External (abnormalities)
• Exome
• Female
• Genes, Dominant
• Haploinsufficiency
• Hearing Loss (genetics)
• High-Throughput Nucleotide Sequencing
• Homeodomain Proteins (genetics)
• Humans
• Male
• Pedigree
• Phenotype