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

J oubert syndrome (JS) is an autosomal recessive disorder presenting with congenital hypotonia evolving into ataxia, developmental delay, and either oculomotor apraxia or abnormalities of respiratory pattern or both. JS is characterised, using magnetic resonance imaging (MRI), by cerebellar vermian hypoplasia and a complex brain stem malformation called the ‘‘molar tooth sign’’ (MTS), consisting of thickened, elongated, and reoriented superior cerebellar peduncles and a deep interpeduncular fossa. JS has been classified into two groups, A and B, the latter being characterised by the occurrence of retinal and/or renal involvement. Key associated features of JS are retinal dystrophy and nephronophthisis, but other manifestations include ocular colobomas, liver fibrosis, and polydactyly. The variable involvement of other organs identifies a large spectrum of syndromes sharing the MTS (such as Arima, COACH, and Senior-Löken syndromes) which, together with JS, are termed Joubert syndrome related disorders (JSRD) or MTS related syndromes. To date, three genetic loci associated with JSRD have been mapped to chromosome 9q34.3 (JBTS1), 11p11.2–q12.3 (JBTS2), and 6q23 (JBTS3). Recently, mutations in the AHI1 gene have been identified in three JBTS3 linked families presenting with a pure cerebellar phenotype. Isolated nephronophthisis (NPH) is an autosomal recessive tubulointerstitial medullary kidney disease and is one of the most frequent monogenic causes of chronic renal failure in childhood. Four genes causing infantile or juvenile NPH have been cloned so far (NPHP1 to 4). Of these, NPHP1 is the most commonly mutated gene, being responsible for at least 50% of cases with juvenile NPH. 16 A large homozygous deletion of the NPHP1 gene is found in more than 80% of patients, while less than 5% are compound heterozygote for the gene deletion and a point mutation on the other allele. Most patients with the NPHP1 deletion demonstrate progressive normotensive renal failure in the second decade of life, associated with severe polyuria and anaemia. Some patients, however, present more complex phenotypes resembling JSRD, such as NPH associated with pigmentary retinopathy (Senior-Löken syndrome), congenital oculomotor apraxia (COGAN syndrome), 19 or cerebellar vermis hypoplasia. 21 Recently, Parisi and colleagues screened 25 patients with JS type B for the NPHP1 deletion, which was found in two siblings with a cerebello-renal phenotype and in an additional sporadic case with NPH and mild psychomotor delay but no cerebellar signs. None of the three patients had retinal involvement. MRIs from all patients showed an MTS characterised by moderate inferior vermis hypoplasia with elongated but not thickened superior cerebellar peduncles. Herein we describe the results of a screening for NPHP1 deletion in a group of Italian patients with various MTS associated phenotypes. METHODS We searched for NPHP1 deletions in 40 probands with JSRD and proven MTS, ascertained through several clinicians participating in the Italian MTS Study Group. As NPH can be asymptomatic for years before manifesting renal insufficiency, we included in the study all patients with a confirmed MTS, independently of the presence of renal involvement. A blood sample was drawn from patients after obtaining written parental informed consent for NPHP1 diagnostic testing. Key points