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HOXA1 Deficiency Syndrome 

HOXA1 Deficiency Syndrome
Chapter:
HOXA1 Deficiency Syndrome
Author(s):

Max A. Tischfield

, Robert P. Erickson

, and Elizabeth C. Engle

DOI:
10.1093/med/9780199934522.003.0089
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date: 25 February 2021

Homeobox A1 (HOXA1), the 3′ most member in the HOXA gene cluster, encodes a transcription factor that is necessary for catalyzing gene expression pathways important for rostral development of the vertebrate embryo. Two syndromes resulting from homozygous HOXA1 mutations, Bosley–Salih–Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome (ABDS), were discovered in patients from three genetically isolated populations in the Middle East and American southwest. It is now clear that they overlap markedly and should be considered one syndrome, HOXA1 Deficiency Syndrome (HDS). Affected individuals have a pleiotropic spectrum of phenotypes including horizontal gaze abnormalities, facial weakness, deafness, hypoventilation, skull deformities, autism, intellectual disabilities, internal carotid artery (ICA) malformations, and conotruncal heart defects (Tischfield et al., 2005, Bosley, et al, 2008). Although horizontal gaze abnormalities and sensorineural deafness are the most penetrant aspects of the syndrome, the remaining phenotypes demonstrate variable expressivity that may be dependent upon genetic background and environment. The identified mutations, two nonsense and one frameshift, all introduce premature stop codons in exon 1 of HOXA1. The predicted truncated mutant proteins lack known functional domains critical for the transcriptional activity of HOXA1 and presumably result in loss of protein function. These findings demonstrate that HOXA1 is indispensable for proper development of the head, nervous system, heart, and cerebrovascular system in humans. In addition, HOXA1 is one of 7 genes involved in oligogenic heterozygosity in individuals with high-functioning autism spectrum disorder (Schaaf, et al, 2008).

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