Genetic findings
Three family members (II-1; father, II-2; mother, and III-1; proband) were selected for ES to be performed in order to identify potential variants responsible for HM in this family. ES analysis revealed a novel heterozygous nonsense mutation inARR4(c.569C>G, p.S190*) in the proband (III-1), which was predicted to produce a shorter, unfinished protein product. This mutation was verified by Sanger sequencing and was found to co-segregate with all affected individuals (Figure 2AD, Table 1). According to ACMG guidelines, and because it belongs to PVS1 (a nonsense variant inARR4 where a loss of function is one mechanism ofARR4- linked HM), PM2 (absent from controls), and PP1 (co-segregation with HM), the novel ARR4 mutation was classified as pathogenic.