Research Article: Co-occurrence of Distinct Ciliopathy Diseases in Single Families Suggests Genetic Modifiers

Date Published: December 14, 2011

Publisher: Wiley Subscription Services, Inc., A Wiley Company

Author(s): Maha S Zaki, Shifteh Sattar, Rustin A Massoudi, Joseph G Gleeson.


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. © 2011 Wiley Periodicals, Inc.

Partial Text

Ciliopathies are recessively inherited conditions that share at their core some dysregulation of structure or function of the cellular primary cilium. Ciliopathies commonly include Leber congenital amaurosis (LCA, i.e. congenital retinal blindness (OMIM #204000), nephronophthisis (NPHP, OMIM #256100), and Joubert syndrome (JS, OMIM #213300). LCA is characterized by congenital blindness due to defective photoreceptors, NPHP is characterized by a fibrocystic transformation of the kidney, whereas JS is characterized by the presence of a pathognomonic “molar tooth” sign (MTS) of the midbrain–hindbrain junction on axial brain imaging. Several overlapping syndromes have been described including Senior–Loken syndrome (LCA + NPHP, OMIM #266900), and cerebellooculorenal syndrome (JS + LCA + NPHP, OMIM #608091) [Valente et al., 2003], suggesting either unique syndromes or variable expressivity.

Patients were ascertained according to approved protocols at National Research Centre, Egypt and the University of California, San Diego. Signed consent was obtained from all participants, and consent was further obtained to allow for reproduction of facial photographs in scientific manuscripts. Intelligence testing was performed using the Stanford–Binet Scale. DNA was extracted from peripheral blood lymphocytes using Qiagen Maxiprep DNA extraction method. PCR was performed using reagents from Qiagen, and DNA sequencing was performed on an ABI 3700 Capillary Sequencer.

There have been six genes reported to cause both NPHP and JS: NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and TMEM216 [Hildebrandt et al., 1997; Dixon-Salazar et al., 2004; Ferland et al., 2004; Parisi et al., 2004; Sayer et al., 2006; Utsch et al., 2006; Valente et al., 2006b; Arts et al., 2007; Baala et al., 2007; Delous et al., 2007; Otto et al., 2009; Valente et al., 2010]. In each case, the gene is primarily associated with one of the two disorders but some percentage of patients with mutations display features of both diseases. In order to exclude Ciliopathy-672 from linkage to any of these loci, we performed SNP genotyping using markers surrounding each of the genes [Murray et al., 2004]. At least two polymorphic markers per gene (rs1718031 and rs729386 for NPHP1; rs1041480 and rs2064430 for AHI1; rs2061589 and rs1508595 for CEP290; rs1990637 and rs1946155 for RPGRIP1L; rs1483457 and rs911 for TMEM67) were inconsistent with linkage in Ciliopathy-672.

We report on two families with at least partial discordance for ciliopathy phenotypes [Badano et al., 2006]. The ciliopathies are an expanding group of partially overlapping clinical entities, unified by the observation both of allelism between what were previously considered separate syndromic conditions, as well as finding that the protein products are localized predominantly to the basal body or cilium of cells from the affected organs [Ansley et al., 2003; Mykytyn and Sheffield, 2004].




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