Fig. 2

Identification of bi-allelic variants in CIROZ in individuals with HTX (A) Pedigrees of 10 families with individuals presenting with heterotaxy (HTX). The CIROZ genotypes for available individuals are indicated. Double lines between symbols indicate consanguineous marriages. Squares, circles, diamonds, and triangles denote males, females, unknown gender individuals, and fetuses, respectively. Open and filled symbols are used for unaffected and affected family members, respectively, and deceased individuals are indicated by a diagonal slash through the symbol. Small black circles indicated spontaneous abortion. The gray question mark indicates a denied consanguinity in family 8. TOP, termination of pregnancy; wt, wild type; mut, mutation. (B) Genomic and protein schematic structures of human CIROZ. The position and nature of the identified variants are indicated. CIROZ known protein domains are highlighted: signal peptide (SP; yellow) and DUF44556 (domain of unknown function, orange). (C) Comparison of the heart phenotype in CIROZ-deficient individuals compared to affected individuals with causative variants in one of the 4 other HTX genes of the module (MMP21, CIROP, PKD1L1, and DAND5). CHDs, congenital heart defects. Only individuals with a confirmed CIROZmut/mut genotype were included in this analysis (n = 16). (D) Comparison of the situs clinical outcome (situs solitus, situs ambiguus, or situs inversus) in individuals with bi-allelic loss-of-function variants in any of the 5 genes of the module (MMP21, CIROP, PKD1L1, DAND5, and CIROZ) or that of 6 genes (CCDC39, CCDC40, DNAH5, DNAH11, DNAI1, and DNAI2) whose bi-allelic mutation leads to primary ciliary dyskinesia (CILD).