Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND:
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.