The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report

• Published in: International journal of molecular sciences 2024-08, Vol.25 (17), p.9348
• Main Authors: Zepeda-Olmos, Paola Montserrat, Robles-Espinoza, Kiabeth, Esparza-García, Eduardo, Magaña-Torres, María Teresa
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Congenital Abnormalities; Ectromelia - genetics; Fingers & toes; Fingers - abnormalities; Foot diseases; Genes; Genetic Association Studies; Genetics; Genotype & phenotype; Hand Deformities, Congenital - genetics; Hedgehog Proteins - genetics; Humans; Infant; limb development; Male; Mandibulofacial Dysostosis; Mutation; Patients; Phenotype; Polydactyly - genetics; Quality of life; SHH; skeletal disorders; Thumb - abnormalities; Tibia - abnormalities; tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS); Toes - abnormalities; Transcription factors; Ultrasonic imaging; ZRS
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25179348

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of . Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.