Iqcb1 (nphp5) Mutations In Leber Congenital Amaurosis With Very Late Nephronophthisis

Abstract

Purpose: : Hitherto, mutations in 13 genes were reported to account for 2/3 of Leber congenital amaurosis (LCA). Mutations in one of them, CEP290 (NPHP6), result in a variety of phenotypes ranging from isolated retinal degeneration to pleiotropic disorders including nephronophthisis (Senior-Løken syndrome; SNLS) and cerebellar vermis aplasia (Joubert syndromes; JBTS). Recently, genetic and physical interactions were reported between CEP290 and IQCB1 (NPHP5) which mutations have been reported to account for SNLS. This finding prompted us to look for IQCB1 mutations in LCA patients.

Methods: : 240 LCA patients with no cerebellar or renal alterations and no mutation in LCA genes were screened for IQCB1 mutations by direct sequencing. Clinical data were updated for renal function.

Results: : 22 IQCB1 disease alleles were identified in 11 families (13 patients; 8 different mutations, 5/8 novel). Consistent but highly variable hyperopia (+3 to +10) was noted. Patients of 7 families were affected with LCA type II (rod-cone dystrophy). Whereas, 3 unrelated cases presented with type I (cone-rod dystrophy). Fundus showed multiple white-dots and/or snail track aspect in the mid-peripheral retina (n=5). Update of renal history revealed nephronophtisis symptoms with early to very late onset in 6/11 families (9 patients; 4 y55 y) while 5/11 families are under investigations (n=7 patients).

Conclusions: : Owing to its onset at birth, LCA is the presenting symptom in several multisystemic disorders which diagnosis is usually made when extraocular symptoms are overt i.e. in the first two decades of life. However, here we report that in SNLS the age at onset of renal failure may vary widely from patient to patient even within families, ranging from early childhood to very late adulthood(>55y). The observation of non exceptional late-onset renal failure requires a close follow-up of patients with IQCB1 mutations whatever their age and more generally of patients whose genotype is unknown. Conversely, the identification of mutations in all LCA genes but CEP290, warrants the absence of risk to develop syndromic LCA making extra-ocular investigations useless.

Keywords: candidate gene analysis • clinical (human) or epidemiologic studies: natural history