Identification of de novo ITPR3 variants in five unrelated patients presenting with CID and ED . (A) Pedigrees of the five unrelated patients included in this study. Females are represented by circles, males by squares, and affected individuals (P1–P5) are denoted by filled, black symbols. P4 (IV) is part of a dizygotic twinship. P5 (V) was conceived using donor sperm. Where known, genotypes are displayed below each individual. (B) Sanger sequencing of genomic DNA confirming the heterozygous ITPR3 variants found in P1–P5; REF = reference sequence, ALT = alternative sequence; representative of two independent experiments. (C) Clinical photographs of P2, P3, P4, and P5 demonstrate some of the associated syndromic features, including dental abnormalities (microdontia, hypodontia, conical teeth, and enamel hypoplasia), nail dystrophy, and deformity of the feet and hands. (D) Flowchart detailing the strategy used to identify patients with heterozygous ITPR3 variants within the rare diseases cohort of the GEL 100,000 Genomes Project (GEL100KGP); Trios = genomes of probands and parents.