Hand-foot-genital syndrome due to a duplication variant in the GC-rich region of HOXA13

Background: Hand-Foot-Genital Syndrome (HFGS) is an autosomal dominant disorder characterized by a broad phenotypic spectrum. Variants in HOXA13 gene were associated with HFGS. To date, only twenty families with HFGS have been reported. However, the challenge in HFGS is the limited sample sizes and phenotypic hetero-geneity. The advent of next-generation sequencing has permitted the identification of patients with HOXA13 variants who do not manifest with the full HFGS syndromic features.Methods: Trio (parents-proband) Whole-exome sequence(WES) and whole-genome sequencing(WGS) was carried out in this study to investigate the underlying pathogenic genetic factor of the neonate with a wide variety of clinical abnormalities.Results: No possible pathogenetic variation was detected by trio-WES, and a duplication variant in HOXA13 (c.360_377dup, p.Ala128_Ala133dup), inherited from her mother, was identified by the subsequent WGS in the proband with malnutrition, feeding difficulties, electrolyte disorders, metabolic acidosis, recurrent urinary tract infections, hydronephrosis, nephrolithiasis, abnormal ureter morphology, cholelithiasis, uterus didelphys. Sequence analysis of the variant region (exon1) indicated a high GC content of 73.92%. In addition, further enquiry of the family history revealed that 5 members of the family in 4 generations had hand and foot anomalies.Conclusion: The neonate was diagnosed with HFGS by genetic analysis. GC content had less influence on sequence coverage in WGS than WES analysis. This was the first report of trio-WGS study for HFGS genetic diagnosis, revealed that subsequent WGS was necessary for identification of potentially pathogenic variants in unexplained genetic disorders.

Automated summary

This study investigated the underlying genetic factors of a neonate with a wide variety of clinical abnormalities using trio (parents-proband) whole-exome sequencing (WES) and whole-genome sequencing (WGS). No possible pathogenic variation was detected by trio-WES, but a duplication variant in HOXA13 (c.360_377dup, p.Ala128_Ala133dup) inherited from the mother was identified by subsequent WGS. Further investigation of the family history revealed hand and foot anomalies in 5 members across 4 generations. The neonate was diagnosed with Hand-Foot-Genital Syndrome (HFGS) based on the genetic analysis.