GLIS Family Zinc Finger 1 was First Linked With Preaxial Polydactyly I in Humans by Stepwise Genetic Analysis.

Preaxial polydactyly (PPD) is one of the most common developmental malformations, with a prevalence of 0.8-1.4% in Asians. PPD is divided into four types, PPD I-IV, and PPD I is the most frequent type. Only six loci (, , , ZRS, pre-ZRS, and a deletion located 240 kb from ) have been identified in non-syndromic PPD cases. However, pathogenesis of most PPD patients has never been investigated. This study aimed to understand the genetic mechanisms involved in the etiology of PPD I in a family with multiple affected members. We recruited a PPD I family (PPD001) and used stepwise genetic analysis to determine the genetic etiology. In addition, for functional validation of the identified variant, studies were conducted. variants were further screened in additional 155 PPD cases. We identified a variant (NM_147193: c.1061G > A, p.R354H) in the PPD001 family. studies showed that this variant decreased the nuclear translocation of GLIS1 and resulted in increased cell viability and migration. RNA sequencing revealed abnormal and expression in 293T cells transfected with mutant GLIS1. Additionally, we identified a variant (c.664G > A, p.D222N) in another PPD case. We identified two variants in PPD I patients and first linked with PPD I. Our findings contributed to future molecular and clinical diagnosis of PPD and deepened our knowledge of this disease.