TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis

Genes (Basel). 2022 Sep 14;13(9):1649. doi: 10.3390/genes13091649.

Abstract

Ulnar-mammary syndrome (UMS) is a rare, autosomal dominant disorder characterized by anomalies affecting the limbs, apocrine glands, dentition, and genital development. This syndrome is caused by haploinsufficiency in the T-Box3 gene (TBX3), with considerable variability in the clinical phenotype being observed even within families. We describe a one-year-old female with unilateral, postaxial polydactyly, and bilateral fifth fingernail duplication. Next-generation sequencing revealed a novel, likely pathogenic, variant predicted to affect the canonical splice site in intron 3 of the TBX3 gene (c.804 + 1G > A, IVS3 + 1G > A). This variant was inherited from the proband’s father who was also diagnosed with UMS with the additional clinical finding of congenital, sagittal craniosynostosis. Subsequent whole genome analysis in the proband’s father detected a variant in the EFNA4 gene (c.178C > T, p.His60Tyr), which has only been reported to be associated with sagittal craniosynostosis in one patient prior to this report but reported in other cranial suture synostosis. The findings in this family extend the genotypic spectrum of UMS, as well as the phenotypic spectrum of EFNA4-related craniosynostosis.

Keywords: EFNA4; TBX3; Ulnar Mammary Syndrome; sagittal craniosynostosis.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Breast Diseases* / genetics
  • Craniosynostoses* / genetics
  • Female
  • Humans
  • T-Box Domain Proteins / genetics
  • Ulna / abnormalities

Substances

  • T-Box Domain Proteins
  • TBX3 protein, human

Supplementary concepts

  • Ulnar-mammary syndrome