Fig. 1

Figure 1. Rare DENND5A variants identified in multicase melanoma families. A. Pedigrees of multicase melanoma families with heterozygous DENND5A variants. +/+ and +/? indicate the tested family members as DENND5A wild types and heterozygotes, respectively. B. A flowchart showing the variant filtering of exome sequencing applied to family A. C. Chromatograms of the validated DENND5A variants found in indicated families. The 1 base pair (bp) insertion (c.2903_2904insG) found in family A is shown on the left, and the 1 bp substitution (c.?680C>T) found in family B is shown on the right in blue. D. Schematic diagram of the positions of identified variants in DENND5A mRNA (upper panel), and the predicted size of truncated protein (p.Ser969fs) derived from the frameshift variant. E. DENND5A amino acid alignments of a variety of species (human, mouse, rat, zebrafish, chimpanzee, goat, chicken, sheep) highlighting the conserved region flanking the frameshift area (shown in red). F. Representative western blotting and quantification (G) of DENND5A protein in EBV-lymphoblastoid cells established from 2 unrelated controls and DENND5A heterozygote individual (III:1) from family A. H. Correlation of cutaneous melanoma incidence rates, and the aggregated deleterious variants frequency in DENND5A, MC1R, MITF, CDKN2A, CDK4, and POT1 across the globe, including Southern Asian, Eastern Asian, African, Latino, Non-Finnish European, Finnish, and Swedish population. Two-tailed, (G) paired t test, (H) Pearson correlation. a.a., amino acid; CDS, coding sequence; EBV, Epstein-Barr virus; LoF, loss of function; MAF, minor allele frequency; mRNA, messenger RNA; NS, not significant; UTR, untranslated region. ?P <.05; ??P <.01.