ORPHA: 3156;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p14 | Senior-Loken syndrome 8 | 616307 | Autosomal recessive | 3 | WDR19 | 608151 |
A number sign (#) is used with this entry because of evidence that Senior-Loken syndrome-8 (SLSN8) is caused by homozygous or compound heterozygous mutation in the WDR19 gene (608151) on chromosome 4p14.
For a general phenotypic description and discussion of genetic heterogeneity of Senior-Loken syndrome, see SLSN1 (266900).
Coussa et al. (2013) studied a consanguineous French Canadian family with an atypical form of retinitis pigmentosa (RP) as well as renal cysts. The 50-year-old male proband had bilateral visual acuities of hand motion only, with severe constriction of visual fields (5 degrees); electroretinographic responses were undetectable. Fundus examination showed fine bone spicules in the periphery and severely attenuated vessels in both eyes, with slight temporal pallor of the optic discs. The patient also exhibited significant macular atrophy that had a 'bear claw' appearance on fundus autofluorescence. Optical coherence tomography (OCT) revealed considerable thinning of the fovea and a poorly delineated photoreceptor layer with extensive loss of the inner/outer segment junctions, as well as foveal debris. Because the patient had a family history of 'kidney problems,' a pelvic ultrasound was performed, which showed bilateral large exophytic renal cysts, although urinalysis and blood biochemistry were within normal ranges. The patient also had mild cognitive impairment. Other family members with RP included the proband's deceased mother, 4 sisters, and a maternal aunt, several of whom also had subclinical renal cysts.
Lee et al. (2015) reported 2 unrelated Korean pediatric patients, a 15-year-old boy (II-1) and a 6-year-old girl (IV-1), with nephronophthisis and retinitis pigmentosa and mutation in the WDR19 gene. Both exhibited hepatic duct dilation and hepatic fibrosis (Caroli syndrome). Renal biopsy in the boy showed chronic tubulointerstitial nephritis with diffuse global glomerulosclerosis involving 40% of glomeruli, and nonspecific immune complex deposits.
The transmission pattern of SLSN8 in the patients reported by Halbritter et al. (2013) was consistent with autosomal recessive inheritance.
In 3 unrelated patients with nephronophthisis and retinal dystrophy, Halbritter et al. (2013) identified biallelic mutations in the WDR19 gene (608151.0006-608151.0007 and 608151.0010-608151.0011). The patients were ascertained from a larger cohort of 1,056 patients with nephronophthisis-related disorders who underwent genetic analysis; 2 of the 3 Senior-Loken patients exhibited additional features of a ciliopathy, with dilation of the intrahepatic bile ducts in 1 and pancreatic and hepatic cysts in the other.
In affected members of a consanguineous French Canadian family with retinitis pigmentosa and renal cysts, who were negative for mutation in all known autosomal recessive RP-associated genes, Coussa et al. (2013) performed whole-exome capture and next-generation sequencing and identified homozygosity for a missense mutation in the WDR19 gene (L710S; 608151.0001). Screening of 96 patients with a diagnosis of Senior-Loken syndrome revealed WDR19 mutations in 5 probands (see, e.g., 608151.0006-608151.0007 and 608151.0012-608151.0013).
By targeted exome sequencing covering 96 ciliopathy-related genes in 48 unrelated Korean pediatric patients with clinical suspicion of nephronophthisis (NPHP), Lee et al. (2015) identified a 15-year-old boy (II-1) with NPHP and RP who was compound heterozygous for 2 missense mutations in the WDR19 gene. One was the previously reported R1178Q variant (608151.0010), and the other was a G495C substitution (608151.0014). Sanger sequencing in an unrelated 6-year-old Korean girl (IV-1) with NPHP and RP revealed homozygosity for the R1178Q variant. Sanger sequencing confirmed the mutations and their segregation with disease in both families, and none was detected in 100 Korean controls or in an in-house exome database of 80 Korean individuals. The authors also identified 4 Korean patients with nephronophthisis and mutation in the WDR19 gene (NPHP13; 614377); noting that all 6 patients showed intrahepatic bile duct dilation and some had hepatic fibrosis as well, the authors concluded that Caroli disease/syndrome might be a major extrarenal phenotype associated with mutations in the WDR19 gene.
Coussa, R. G., Otto, E. A., Gee, H.-Y., Arthurs, P., Ren, H., Lopez, I., Keser, V., Fu, Q., Faingold, R., Khan, A., Schwartzentruber, J., Majewski, J., Hildebrandt, F., Koenekoop, R. K. WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome. Clin. Genet. 84: 150-159, 2013. [PubMed: 23683095] [Full Text: https://doi.org/10.1111/cge.12196]
Halbritter, J., Porath, J. D., Diaz, K. A., Braun, D. A., Kohl, S., Chaki, M., Allen, S. J., Soliman, N. A., Hildebrandt, F., Otto, E. A., The GPN Study Group. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum. Genet. 132: 865-884, 2013. [PubMed: 23559409] [Full Text: https://doi.org/10.1007/s00439-013-1297-0]
Lee, J. M., Ahn, Y. H., Kang, H. G., Ha, I. I., Lee, K., Moon, K. C., Lee, J. H., Park, Y. S., Cho, Y. M., Bae, J. S., Kim, N. K., Park, W.-Y., Cheong, H. I. Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney. Pediat. Nephrol. 30: 1451-1458, 2015. [PubMed: 25726036] [Full Text: https://doi.org/10.1007/s00467-015-3068-8]