Mutations in HOXA1 can lead to diseases such as Bosley-Salih-Alorainy syndrome, involving severe cardiovascular malformations. However, the role of HOXA1 in cardiac morphogenesis remains unclear. hoxa1a is a homologous gene to human HOXA1 in zebrafish. We used CRISPR to make hoxa1a-null zebrafish that exhibited multiple heart malformations. In situ hybridization and sections revealed the morphological changes in mutants: enlarged ventricle with thickened myocardium and increased trabeculae, intensified OFT and inadequate heart looping, with electrocardiography supporting these pathological changes. High-speed photography captured cardiac pumping and revealed a significant decrease in cardiac output. Furthermore, lacking hoxa1a led to posterior body abnormality that affected movement ability, corresponding with the motor development delay in patients. Upregulation of hox paralogues in hoxa1a-null fish implied a compensatory mechanism between hox genes. Accordingly, we successfully constructed a hoxa1a-null model with a cardiac disease pattern which occurred in human HOXA1-associated heart malformation. The study of hoxa1a in zebrafish can further promote the understanding of hox genes and related diseases.

With the advent of cochlear implants, tactile aids for the profoundly deaf became obsolete decades ago. Nevertheless, they might still be useful in rare cases. We report the case of a 25-year-old woman with Bosley-Salih-Alorainy Syndrome and bilateral cochlear aplasia. After it was determined that cochlear or brainstem implants were not an option and tactile aids were not available anymore, a bone conduction device (BCD) on a softband was tried as a tactile aid. The usual retroauricular position and a second position close to the wrist, preferred by the patient, were compared. Sound detection thresholds were measured with and without the aid. Additionally, three bilaterally deaf adult cochlear implant users were tested under the same conditions. At 250-1000 Hz, sounds were perceived as vibrations above approximately 45-60 dB with the device at the wrist. Thresholds were approximately 10 dB poorer when placed retroauricularly. Differentiation between different sounds seemed difficult. Nevertheless, the patient uses the device and can perceive loud sounds. Cases where the use of tactile aids may make sense are probably very rare. The use of BCD, placed, e.g., at the wrist, may be useful, but sound perception is limited to low frequencies and relatively loud levels.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.