Pedigrees, clinical features, and variant analysis. (A) Pedigrees of the four families. Black symbols denote affected individuals, red symbols denote more severely affected individuals. Arrows point to probands in each family. Genotypes are indicated for those individuals who consented to participate in the study. Below are electropherograms obtained through direct sequencing of HMCN1 that revealed a heterozygous G>A transition (arrow) at position c.11905 of the cDNA sequence in individual III–1, family 1, a heterozygous G>A transition (arrow) at position c.8815 of the cDNA sequence in individual II-6, family 2, as well as a heterozygous C>T transition (arrow) at position c.12250 of the cDNA sequence in individual II-2, family 4 (middle panels). The WT sequences (WT/WT) are given for comparison (lower panels). (B) Mildly affected individuals featured plantar involvement only while more severe cases carry variants in HMCN1 and showed at the same age, severe involvement of the hands and additional skin areas. (C) The predicted amino acid changes and the location of the three variants are depicted along a schematic representation of hemicentin-1 and its domains (SP, signal peptide; H, hemicentin domain; IGLR, tandem Ig-like repeat; TSP1, thrombospondin type1 repeat domain; G2F, G2 fragment domain; FC, fibulin carboxy-terminal domains; modified from Xu et al. [2013]).