Genetic and phenotypic continuum of HOXA genes: A case with double HOXA9/HOXA13 mutations

The HOXA genes cluster plays a key role in embryologic development. Mutations in HOXA genes have been linked to different human phenotypes, including developmental delay, limb anomalies, and urogenital malformations. The present study reported a clinical and genetic investigation of a female patient with polymalformative syndrome including left arm agenesis, bicornuate uterus and bicuspid aortic valve. Using whole exome sequencing, two heterozygous missense variants were identified. Of these, one was a novel variant in the HOXA13 gene [p.(Tyr290Ser)] and the second a heterozygous variant in the HOXA9 gene [p.(Ala102Pro)]. To the best of our knowledge, this is the first association of HOXA9/HOXA13 point mutations linked to a syndromic case. In conclusion, the present study suggested that the phenotypic spectrum of vertebral anomalies, anal atresia, cardiac defects, tracheo‑esophageal fistula, renal anomalies and limb abnormalities/hand‑foot‑genital syndrome may be attributable to the combination of different HOXA variants, particularly in patients with a severe clinical presentation. The current report contributed as well to the molecular understanding of HOXA genes‑related phenotypes via the identification of novel variant and genes associations.