HOXA1 – Human HOXA1 Syndromes

HOXA1 encodes a homeobox transcription factor essential for early hindbrain patterning and craniofacial development. Biallelic truncating variants in HOXA1 cause the autosomal recessive human HOXA1 syndromes, including Bosley-Salih-Alorainy syndrome and Athabascan brainstem dysgenesis syndrome. Affected individuals present with segmental rhombomere malformations leading to facial weakness, horizontal gaze palsy, and sensorineural hearing loss. Intellectual disability ranges from mild to moderate, reflecting brainstem anomalies. Cardiac defects are observed in a subset, broadening the phenotypic spectrum. Initial reports described nine individuals from six families carrying homozygous HOXA1 variants ([PMID:18412118]). Subsequent cases include two siblings with a novel exon 2 frameshift allele, confirming recurrence in a different population ([PMID:32864817]).

Genetic evidence derives from multiple unrelated pedigrees segregating homozygous loss-of-function HOXA1 alleles. In the original cohort, nine probands from six families harbored homozygous nonsense or frameshift variants (e.g., c.76C>T (p.Arg26Ter)) that co-segregated under autosomal recessive inheritance ([PMID:18412118]). A follow-up study reported two siblings with a novel exon 2 frameshift variant in HOXA1 ([PMID:32864817]). No heterozygous carriers exhibit the full syndromic phenotype, consistent with a recessive loss-of-function mechanism. The total proband count reaches eleven individuals from seven families, with segregation confirmed by Sanger sequencing.

The clinical phenotype includes horizontal gaze palsy, facial weakness, and sensorineural hearing loss (HP:0000365), mild intellectual disability (HP:0001256), and congenital heart malformations such as conotruncal defects or septal defects (HP:0001627). Craniofacial dysmorphisms and branchial arch anomalies further characterize the syndrome. Phenotypic variability across families suggests possible modifier effects, but the core triad remains highly penetrant.

Functional studies in Hoxa1-null mice recapitulate key human features, demonstrating disrupted rhombomeric segmentation, loss of rhombomeres 4 and 5, and craniofacial branchial arch defects ([PMID:10529420]). These animal models exhibit cardiac outflow tract malformations and impaired neural crest migration, aligning with human cardiac and neurocranial anomalies. In vitro assays of HOXA1 homeodomain mutants show reduced DNA binding and transcriptional activation, supporting a loss-of-function mechanism. Pentapeptide insertion and polyhistidine tract studies further implicate disrupted cofactor interactions in HOXA1 dysfunction.

A targeted sequencing study of 340 Chinese children with isolated ventricular septal defect found no pathogenic HOXA1 coding variants, observing only synonymous and histidine-tract polymorphisms in patients and controls ([PMID:22777240]). This suggests that isolated VSD may not reliably implicate HOXA1 outside of the full syndromic context. No studies have refuted the core association between homozygous truncating HOXA1 alleles and the multisystem syndromic phenotype.

In summary, there is strong clinical and experimental evidence that autosomal recessive HOXA1 loss-of-function variants cause human HOXA1 syndromes. Eleven probands from seven families with consistent truncating alleles, together with concordant mouse model data, satisfy ClinGen criteria for a strong gene-disease association. Genetic testing for HOXA1 should be prioritized in patients presenting with the BSAS/ABDS phenotype. Functional assays reinforce a loss-of-function mechanism. Key Take-home: Homozygous truncating HOXA1 alleles underlie a clinically actionable AR syndrome with defined neuro-cranio-cardiac features.

References

• American journal of medical genetics. Part A | 2008 | The clinical spectrum of homozygous HOXA1 mutations. PMID:18412118
• 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
• Pediatric cardiology | 2013 | HOXA1 gene is not potentially related to ventricular septal defect in Chinese children. PMID:22777240

Evidence Based Scoring (AI generated)