Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B

Abstract

Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement, including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation, polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described as causative in more than 80% of patients. Since different combinations of the extrarenal symptoms with NPH occur in JSB, a contiguous gene deletion syndrome in the NPH1 genetic region would seem a highly likely cause for JSB. We therefore examined 11 families with JSB for the presence of extended deletions at the NPH1 locus. Genomic DNA was examined using four consecutive polymerase chain reaction (PCR) markers that are deleted in NPH1 and three PCR makers flanking the NPH1 deletion. In all seven markers examined, there was no homozygous deletion detected in any of the 11 JSB families studied. Since these markers saturate the NPH1 deletion region at high density, this finding excludes the presence of large homozygous deletions of the NPH1 region in these JSB families, making it unlikely that deletions of the NPH1 region are a primary cause for JSB.

NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders

“…This low frequency is confirmed by a previous study, which failed to detect NPHP1 deletions in 13 patients with JS type B. 24 It should be noticed that juvenile NPH can have a prolonged sub-clinical course until renal insufficiency develops and progress to end-stage renal failure, usually in the second decade of life. Therefore, recognition of renal involvement in patients with JS can be difficult in young children, such as in our patient, who only presented with mild polyuria.…”

Joubert-like syndrome unlinked to known candidate loci

“…[11][12][13][14][15] An association of CVH with both chorioretinal coloboma and renal disease has also been reported in 15 patients including four sib pairs. 7, [16][17][18][19][20][21] The renal abnormalities in these cases were variably described as medullary cystic renal disease, as mild autosomal recessive polycystic kidney disease, as nephronophthisis, and as interstitial fibrosis. In these patients, abnormal eye movements and mental retardation were also recorded.…”

Joubert syndrome (and related disorders) (OMIM 213300)

“…In contrast, juvenile nephronophthisis is characterized by microscopic cysts affecting the renal tubules and usually presents with urine concentrating defects in the first or second decade of life manifested by polydipsia, polyuria, anemia, and growth failure, with progression to end-stage renal disease by B13 years of age. 25,26 Small, scarred, and echogenic kidneys on ultrasound are only visible late in the course of the disease. Although these two renal lesions have been considered distinct, one report reviewed the renal pathology that had been described as cystic dysplasia in subjects with DekabanArima syndrome and found it to be indistinguishable from nephronophthisis.…”