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.