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Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia
Dennis C Monks1, Arthee Jahangir, Alan L Shanske
1Division of Translational Genetics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Price Center 402, Bronx, NY 10461, USA.
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.
Insights
Genetic analysis of HOXA2 and SIX2 genes did not reveal mutations causing sporadic microtia in Hispanic and African American patients. Novel variants were identified but ruled out as causal, suggesting other genetic factors may be involved.
Area of Science:
- Genetics
- Developmental Biology
- Otolaryngology
Background:
- Microtia, a congenital external ear malformation, has varied prevalence, with higher incidence reported in Hispanic and African American populations.
- No specific genetic mutations have been identified as causal for microtia in these understudied ethnic groups.
- Homeobox genes HOXA2 and SIX2 are implicated in ear development and are potential candidates for microtia-related mutations.
Purpose of the Study:
- To investigate whether mutations in the HOXA2 and SIX2 genes are responsible for sporadic cases of microtia.
- To analyze the coding regions and regulatory elements of HOXA2 and SIX2 in patients of Hispanic and African descent.
Main Methods:
- DNA sequencing of HOXA2 and SIX2 exons was performed on 8 patients of Hispanic and African descent with sporadic microtia.
- Identified variants were further analyzed in an additional 4 patients and 100 Hispanic controls using Sequenom MassArray.
- Sequencing focused on coding regions, introns, and UTRs (untranslated regions) of the candidate genes.
Main Results:
- No causative mutations were found in the coding sequences of HOXA2 or SIX2 in the studied microtia patients.
- Four novel single nucleotide variants were identified in the intron and UTRs of HOXA2 and SIX2.
- All identified novel variants were also present in Hispanic control samples, excluding them as disease-causing mutations.
Conclusions:
- The studied sporadic microtia cases likely result from etiologies other than mutations in the coding regions of HOXA2 and SIX2.
- The discovery of novel variants in Hispanic populations highlights potential genetic diversity and the need for further research in underrepresented groups.
- Genetic factors contributing to microtia may differ across ethnic populations, necessitating population-specific genetic analyses.
