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Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development


We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

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Figure 1: Clinical and radiological features of BSAS.
Figure 2: Schematic representation of three reported human HOXA1 isoforms and corresponding predicted mutant proteins.

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We thank the family members for their participation; H. Kinney, R. Robertson, K. Yamada, H. Etchevers, J. Tischfield and C. Walsh for discussions and manuscript review; and C. Dow for technical expertise. This work was supported by the US National Institutes of Health (E.C.E.) and the Muscular Dystrophy Association and the Holslaw Family Professorship (R.P.E.).

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Correspondence to Elizabeth C Engle.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

HOXA1 syndrome pedigrees and electropherograms. (PDF 1108 kb)

Supplementary Table 1

Clinical summary of BSAS patients. (PDF 53 kb)

Supplementary Table 2

Primer sequences. (PDF 62 kb)

Supplementary Table 3

Two-point lod scores between the BSAS locus and 7p markers. (PDF 47 kb)

Supplementary Methods (PDF 116 kb)

Supplementary Note (PDF 90 kb)

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Tischfield, M., Bosley, T., Salih, M. et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37, 1035–1037 (2005).

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