HOXA1 – Bosley-Salih-Alorainy Syndrome

Bi-allelic loss-of-function variants in HOXA1 underlie the autosomal recessive Bosley-Salih-Alorainy syndrome, a congenital human HOXA1 syndrome characterized by horizontal gaze limitation (Duane retraction), facial nerve palsy, and sensorineural hearing loss. Early case series identified truncating HOXA1 mutations in multiple consanguineous families, establishing a clear gene-disease relationship ([PMID:18412118]; [PMID:17875913]; [PMID:32864817]).

Genetic evidence supports autosomal recessive inheritance with segregation of homozygous truncating alleles across 12 families and 20 affected individuals. Three distinct truncating variants have been reported: c.175dup (p.Val59fs) ([PMID:18412118]), c.185del (p.Gly62fs) ([PMID:18412118]), and c.76C>T (p.Arg26Ter) ([PMID:18412118]). A recurrent I75-I76insG frameshift was identified in nine Saudi Arabian patients ([PMID:17875913]), and two Indian siblings harbor a novel exon 2 pathogenic variant ([PMID:32864817]).

The phenotypic spectrum includes bilateral Duane retraction syndrome type 3, inner ear malformations with bilateral deafness (HP:0000365), congenital heart malformations in 4/9 BSAS patients (HP:0001627) ([PMID:18412118]), mild intellectual disability (HP:0001256) in Athabascan brainstem dysgenesis syndrome ([PMID:18412118]), and motor delay (HP:0001270) in Saudi families ([PMID:17875913]). Clinical variability and occasional isolated cardiovascular presentation have been observed.

Functional studies demonstrate that Hoxa1 knockout mice exhibit loss of rhombomeres 4–5 and branchial arch derivatives, recapitulating human hindbrain and cranial nerve defects ([PMID:10529420]). Homeodomain mutagenesis assays reveal that key residues are required for transcriptional activation on developmental enhancers, consistent with a loss-of-function mechanism ([PMID:12060683]).

Pathogenic HOXA1 variants truncate the homeodomain or disrupt cofactor binding motifs, leading to failed hindbrain patterning and cranial nerve development. Concordant in vivo and in vitro data establish haploinsufficiency for homozygous alleles as the pathogenic mechanism.

Genetic testing for HOXA1 bi-allelic variants enables definitive diagnosis of BSAS, informs surveillance for audiovestibular and cardiac anomalies, and supports family counseling and carrier screening in high-risk populations.

Key Take-home: Autosomal recessive HOXA1 loss-of-function variants cause Bosley-Salih-Alorainy syndrome with hallmark ocular motility and hearing defects, supported by robust genetic segregation and functional evidence.

References

• American journal of medical genetics. Part A • 2008 • The clinical spectrum of homozygous HOXA1 mutations. PMID:18412118
• Neurology • 2007 • Clinical characterization of the HOXA1 syndrome BSAS variant. PMID:17875913
• American journal of medical genetics. Part A • 2020 • Bosley-Salih-Alorainy syndrome in patients from India. PMID:32864817
• Development (Cambridge, England) • 1999 • Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. PMID:10529420
• Nucleic acids research • 2002 • Changing homeodomain residues 2 and 3 of Hoxa1 alters its activity in a cell-type and enhancer dependent manner. PMID:12060683

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