Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
Primary objective:

 -  assessment of the prevalence of AHI1 mutations in Joubert syndrome and
 cerebello-oculo-renal syndromes (JS/CORS)

 Secondary objective:

 -  assessment of the prevalence of CEP290 mutations and NPHP1 homozygous deletions in
 JS/CORS

 -  caracterization of mutational spectrum of AHI1, NPHP1, CEP290 genes in JS/CORS.

 -  evaluation of genotype-phenotype correlation in JS/CORS.
Design: multicentric Aims of this study: to describe clinical and genetic basis of Joubert
 syndrome and cerebello-oculo-renal syndromes.Joubert syndrome (JS) is characterized by
 hypotonia, abnormal ocular movements and neonatal breathing dysregulation evolving into
 developmental delay, ataxia, oculomotor apraxia with variable mental retardation. The
 neuroradiological hallmark of JS is a complex midbrain-hindbrain malformation consisting of
 vermis hypoplasia/dysplasia, a deepened interpeduncular fossa, and thickened, elongated and
 mal-orientated superior cerebellar peduncles (Molar Tooth Sign, MTS). Other organs could be
 involved in JS (kidneys :nephronophthisis or cystic dysplastic kidneys; eyes : Leber
 Congenital Amaurosis, retinopathy, colobomas); liver : hepatic fibrosis; others: polydactyly,
 tongue hamartomas, situs inversus). Several associated central nervous system malformations
 were described : polymicrogyria, hydrocephalus, corpus callosum anomalies and encephalocele.
 This pleiotropic involvement identifies a large spectrum of cerebello-oculo-renal syndromes
 or JS Related Disorders (JSRD).

 Joubert syndrome and cerebello-oculo-renal syndromes (JS/CORS) are autosomal recessive
 conditions associated with a high risk of recurrence for further pregnancies (25%). In 2004
 mutations in AHI1 gene (Abelson helper integration site gene) were identified in 7-11% JS but
 the disease is caracterized by a wide genetic heterogeneity. At least five others genes are
 involved in JS/CORS : NPHP1, which homozygous deletions are responsible for a small
 percentage of JS (2%) and more recently CEP290 gene which exact mutations prevalence remained
 to be evaluated.

 Using molecular analysis of those three genes (sequencing of 29 coding exons of AHI1 and 54
 exons of CEP290, searching for NPHP1 homozygous deletions by PCR analysis) we project to
 study respective prevalence of mutations of those three genes and described associated
 phenotypes in 65 JSCORS patients. This work will allowed to described genotype-phenotypes
 correlation in JSCORS and to progress in the characterization of the underlying pathogenetic
 mechanisms. It will be the first step before identification of novel disease genes.
Inclusion Criteria:

 -  Child or adult patients without age maximum

 -  Affected with JS/CORS défined by neurologic disease with at least one of the following
 symptoms :

 -  neonatal hypotonia or developmental delay (before age 3) or mental retardation
 (QD<70) (after age 3).

 -  Ataxia

 -  Oculomotor apraxia

 -  and on MRI :

 -  vermis hypoplasia/agenesia defined by insufficient development of cerebellar
 vermis.

 -  And molar tooth defined by thickened, elongated and mal-orientated superior
 cerebellar peduncles on axial sections.

 Exclusion Criteria:

 -  Chromosomal anomalies identified by caryotype

 -  Absence of signature of informed consent.

 -  Absence of affiliation to social security