Fig. 1

Recessive frameshift mutations in FAT1 cause a new clinical syndrome. Pedigree of family 1–5 (a). A schematic of human FAT1 start/stop codon, exons, location of mutations previous published and identified in this study (top panel). The FAT1 protein is 4588 amino acids long and contains 34 cadherin repeats (CA), followed by five epidermal growth factor (EGF)-like repeat domains (E), a laminin G domain (LamG), a transmembrane domain (green), and an intracellular domain (bottom panel). Family 1 and 2 were found to carry the same homozygous frameshift variant c.2207dupT (p.I737NfsX7) in FAT1 (NM_005245). In Families 3–5 we identified, respectively, the following homozygous frameshift FAT1 variants: c.2600_2601delCA (p.T867IfsX4), c.9729del p.(V3245LfsX25), and c.3093_3096del (p.P1032CgsX11). H homozygous, h heterozygous (b). Ophthalmic features observed in patients included ptosis; bilateral in patients F1-IV-1, F1-IV-3, F1-IV-5, F2-III-3, F2-IV-3, F3-IV-1 and unilateral in F2-IV-1, F4-II-3 (c), microphthalmia (d), iris coloboma (e), large chorioretinal coloboma containing the papilla/optic nerve with two other smaller circumscribed chorioretinal colobomas localized above the papilla (f), and retinal coloboma (g). Skeletal abnormalities included syndactyly in the majority of patients and bone fusion of phalanges 3–4 on the right foot and hypotrophy of phalanx 2 of the left foot in patient F3-II-2 (h). X-ray of the feet demonstrating cutaneous syndactyly in patient F2-IV-1 (i)