title: Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia.
abstract: OBJECTIVE
  Microtia is a developmental malformation of the external ear with genetic and environmental causes. The prevalence of microtia varies but several studies suggest increased incidence in Hispanic and African American populations. No causal genetic mutations have been identified in these populations. Mutations in the homeobox gene HOXA2 caused microtia in a single Iranian family. Another homeobox gene, SIX2, acts downstream of HOXA2 during development and provides another possible candidate for mutational analysis.
  
  
  METHODS
  To determine whether mutations in HOXA2 or SIX2 cause sporadic microtia, DNA sequencing analysis was performed on exons in both genes in 8 patients of Hispanic and African descent in the Bronx. Identified variants were assayed in an additional 4 patients and 100 Hispanic control samples using Sequenom MassArray to rule out causality in heterozygous patients.
  
  
  RESULTS
  No mutations were identified in the coding sequence of HOXA2 or SIX2. Four novel single nucleotide variants were identified among the patient samples. These variants lie in the intron and 3' UTR of HOXA2 and the 5' and 3' UTRs of SIX2. One variant in the intron of HOXA2 lies in a conserved predicted transcription factor binding site for SMARCA3. All four variants are also present at >5% frequency in Hispanic control samples, ruling out these novel variations as causal.
  
  
  CONCLUSIONS
  Lack of mutations in the coding regions of HOXA2 or SIX2 among the sporadic microtia patients studied indicate different etiologies. Identification of four novel single nucleotide polymorphisms in patients and controls of Hispanic descent, but not of Caucasian populations, points to genetic diversity in an understudied population.
authors.affiliation: Division of Translational Genetics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Price Center 402, Bronx, NY 10461, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Monks
authors.forename: Arthee
authors.initials: A
authors.lastname: Jahangir
authors.forename: Alan L
authors.initials: AL
authors.lastname: Shanske
authors.forename: Joy
authors.initials: J
authors.lastname: Samanich
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
authors.forename: Melanie
authors.initials: M
authors.lastname: Babcock
mesh_terms: D001741:Black or African American / Q000235:genetics; D015331:Cohort Studies; D000013:Congenital Abnormalities; D065817:Congenital Microtia; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities; D004431:Ear, External / Q000002:abnormalities*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006630:Hispanic or Latino / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009519:New York City / Q000453:epidemiology; D018570:Risk Assessment; D017678:Sex Distribution; D014505:Urban Population; D044465:White People / Q000235:genetics
chemical_list: C520321:HOXA2 protein, human; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C484762:SIX2 protein, human