Multimorbidity due to novel pathogenic variants in the WFS1/RP1/NOD2 genes: autosomal dominant congenital lamellar cataract, retinitis pigmentosa and Crohn's disease in a British family

Abstract

Background: A five generation family has been analysed by whole exome sequencing (WES) for genetic associations with the multimorbidities of congenital cataract (CC), retinitis pigmentosa (RP) and Crohn's disease (CD).

Methods: WES was performed for unaffected and affected individuals within the family pedigree followed by bioinformatic analyses of these data to identify disease-causing variants with damaging pathogenicity scores.

Results: A novel pathogenic missense variant in WFS1: c.1897G>C; p.V633L, a novel pathogenic nonsense variant in RP1: c.6344T>G; p.L2115* and a predicted pathogenic missense variant in NOD2: c.2104C>T; p.R702W are reported. The three variants cosegregated with the phenotypic combinations of autosomal dominant CC, RP and CD within individual family members.

Conclusions: Here, we report multimorbidity in a family pedigree listed on a CC register, which broadens the spectrum of potential cataract associated genes to include both RP1 and NOD2.

Keywords: Genetics; Lens and zonules; Retina; Vision.

Figure 1

Abridged pedigree presenting with lamellar CC, RP and CD. Squares and circles symbolise male and female family members, respectively. Open and filled symbols indicate unaffected and affected individuals. All affected individuals had cataract; individuals III-2, IV-2, IV-5, IV-7, V-2, V-4, V-5, V-6 and V-7 had RP and individuals IV-2, IV-5, V-3, V-4 and V-7 had NOD2 variant for CD. Arrows indicate those family members who participated in the WES analysis. CC, congenital cataract; CD, Crohn’s disease; NOD, nucleotide oligomerization domain; RP, retinitis pigmentosa; WES, whole exome sequencing.

Figure 2

Variant identification by sequence analysis: (a) WFS1–missense variant c.1897G>C in affected member, (b) WFS1 wild type in unaffected members; (c) RP1–nonsense variant at c.6344T>G in affected members; (d) wild type RP1 in unaffected members; (e) NOD2–missense variant c. 2104C>T in affected member and (f) NOD2 wild type in unaffected members. NOD, nucleotide oligomerization domain; RP, retinitis pigmentosa.