RT Journal Article
SR Electronic
T1 Mutations in 3 genes (<em>MKS3</em>, <em>CC2D2A</em> and <em>RPGRIP1L</em>) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 8
OP 21
DO 10.1136/jmg.2009.067249
VO 47
IS 1
A1 D Doherty
A1 M A Parisi
A1 L S Finn
A1 M Gunay-Aygun
A1 M Al-Mateen
A1 D Bates
A1 C Clericuzio
A1 H Demir
A1 M Dorschner
A1 A J van Essen
A1 W A Gahl
A1 M Gentile
A1 N T Gorden
A1 A Hikida
A1 D Knutzen
A1 H Özyurek
A1 I Phelps
A1 P Rosenthal
A1 A Verloes
A1 H Weigand
A1 P F Chance
A1 W B Dobyns
A1 I A Glass
YR 2010
UL http://jmg.bmj.com/content/47/1/8.abstract
AB Objective To identify genetic causes of COACH syndromeBackground COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).Methods In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.Results 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).Conclusions Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.