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

Joubert syndrome (JS) is a neurological disorder characterised by a complex cerebellar and brainstem malformation, the so called ‘‘molar tooth sign’’ (MTS). JS can be associated with several abnormalities in other organs, identifying a large spectrum of ‘‘Joubert syndrome related disorders’’ (JSRD). Isolated nephronophthisis (NPH) is an autosomal recessive tubulointerstitial medullary cystic kidney disease, which can be found in some JSRD. Among the four genes responsible for isolated NPH (NPHP1–4), NPHP1 deletions have been found in two families with JS plus NPH. N We tested 40 JSRD probands with proven MTS for NPHP1 deletions. Homozygous deletions were tested by performing two multiplex PCR with two microsatellite markers (one control marker and one internal deletion marker) resolved on agarose gel. Five markers within the common NPHP1 deletion region were genotyped to test heterozygous deletions. N A single NPHP1 homozygous deletion was found in a patient presenting with cerebellar, retinal, and kidney involvement, while heterozygous deletions were excluded in the others. The appearance of MTS in the patient with NPHP1 deletion was characteristic with moderate cerebellar vermis hypoplasia and elongated but not thickened superior cerebellar peduncles. N We confirm that NPHP1 deletions can be a rare cause of JSRD and broaden the NPHP1 associated clinical spectrum. In all NPHP1 JSRD patients so far reported, the MTS shows remarkably similar features, which might be specifically associated with NPHP1 deletions.