Engle Laboratory
Learn about HOXA1-related syndromes
Clinical description
Colleagues in Saudi Arabia and Turkey originally brought this syndrome to our attention because patients all had moderate to severe Duane syndrome Type III, an eye movement disorder that restricts horizontal gaze. Most patients also have bilateral sensorineural hearing loss due to absent cochleas and rudimentary inner ear development.
Left: normal inner ear showing a cochlea (double arrows), vestibule (open arrow) and lateral semicircular canal (single arrow)
Right: This proband had a common cavity defect characterized by an absent cochlea, vestibule and semicircular canals.
Internal carotid artery malformations are present in many patients, and can vary in severity from unilateral hypoplasia to bilateral agenesis.
Left: Normal internal carotid arteries (ICA's)
Right: bilateral absence (right) of the ICA's
Depending upon ethnicity, a subset of patients manifest moderate to severe central hypoventilation, and some have facial weakness, swallowing difficulties, vocal cord paresis, and conotruncal heart defects. Skull and craniofacial abnormalities, including facial asymmetry and external ear defects, can also segregate with the clinical findings above. Finally, autism spectrum disorder and mental retardation are found in some patients.
Genetics
We carried out SNP-based linkage analysis in a Saudi Arabian family and identified a single, fully informative 9-Mb region on 7p15.3-p14.3 in which only the affected children were homozygous. Further analysis using micro-satellite markers and DNA from other similarly affected Saudi Arabian pedigrees identified a haplo-identical region of approximately 300 kb on 7p15.2, suggesting a founder mutation might exist in this population.
Affymetrix 10K SNP Mapping Array
Within this 300 kb haplo-identical region we analyzed HOXA1 for mutations and identified a homozygous guanine insertion, 175-176insG, predicted to result in a reading frameshift and the introduction of a premature stop codon in exon 1. Following this, we identified two additional HOXA1 mutations in one Turkish and several Native American pedigrees. We predict that these mutations result in truncated mutant proteins lacking all known functional domains, thereby resulting in a complete loss of HOXA1 function.
This work was carried out by our graduate student, Max Tischfield.
References
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last updated 12/15/2003 (entry number #*142955 ).
Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
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