AUTHOR=Guo Ruiji , Fang Xia , Mao Hailei , Sun Bin , Zhou Jiateng , An Yu , Wang Bin 

TITLE=A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.731278

DOI=10.3389/fgene.2021.731278

ISSN=1664-8021

ABSTRACT=Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2 and SPD3. SPD1 is caused by HOXD13 mutations which is a homeobox transcription factor crucial for limb development. Over 143 SPD patients have been reported to carry HOXD13 mutations but there is a lack of genotype-phenotype correlation. We reported a novel missense mutation of c. 925A>T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and other three different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension tending to form α-helix and causing protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A>T mutation impaired downstream transcription of EPHA7. We compiled literature findings and analyzed genotype-phenotype features in 173 SPD individuals of 53 families, including the 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%) followed by missense mutations (32%) mostly in the homeobox compared to the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classical SPD was associated with polyalanine mutations, while missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype-phenotype correlation related to the HOXD13 mutation site provides clinical insight including genetic counseling.