Co-occurrence of distinct ciliopathy diseases in single families suggests genetic modifiers

Abstract

Disorders within the "ciliopathy" spectrum include Joubert (JS), Bardet-Biedl syndromes (BBS), and nephronophthisis (NPHP). Although mutations in single ciliopathy genes can lead to these different syndromes between families, there have been no reports of phenotypic discordance within a single family. We report on two consanguineous families with discordant ciliopathies in sibling. In Ciliopathy-672, the older child displayed dialysis-dependent NPHP whereas the younger displayed the pathognomonic molar tooth MRI sign (MTS) of JS. A second branch displayed two additional children with NPHP. In Ciliopathy-1491, the oldest child displayed classical features of BBS whereas the two younger children displayed the MTS. Importantly, the children with BBS and NPHP lacked MTS, whereas children with JS lacked obesity or NPHP, and the child with BBS lacked MTS and NPHP. Features common to all three disorders included intellectual disability, postaxial polydactyly, and visual reduction. The variable phenotypic expressivity in this family suggests that genetic modifiers may determine specific clinical features within the ciliopathy spectrum.

FIG. 1

A: Pedigree of ciliopathy-672, showing first cousin marriage with two affected members in Branch I, NPHP in IV-1, and JS in IV-2. After the death of the mother of Branch I, the father remarried (Branch II) and had three boys, two affected with NPHP. B: Pedigree of ciliopathy-1491, showing first-cousin marriage and three affected children. The oldest displays classic features of BBS, and the younger two display the MTS.

FIG. 2

Facial appearance of affected members from Ciliopathy-672, showing absence of dysmorphic features.

FIG. 3

Clinical features from Ciliopathy-1491. IV-1 shows obesity and bilateral upper and lower extremity postaxial polydactyly. IV-2 shows ptosis of the right eye. IV-3 shows self-inflicted abrasions of the perioral region and postaxial polydactyly of the right hand only.

FIG. 4

Brain MRI of affected members of both families (axial view at the midbrain-hindbrain junction (top) and midline sagittal (bottom)). In Ciliopathy-672, MTS is evident only in IV-2 (arrows), and is absent in IV-1, -3, and -4. There is a small arachnoid cyst evident in IV-3 (arrowhead), not seen in the other members. Consistent with the axial views, only IV-2 shows a horizontally oriented superior cerebellar peduncle (arrow). Despite the absence of the MTS, there is mild cerebellar affection at lest for IV-1. In Ciliopathy-1491, MTS is evident in IV-2 and -3 (arrows) evidence by the horizontally oriented superior cerebellar peduncle (arrows). In IV-1 there is mild cerebellar vermis hypoplasia without the MTS.