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Case Reports
. 2010 Jan;47(1):8-21.
doi: 10.1136/jmg.2009.067249. Epub 2009 Jul 1.

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

D Doherty  1 , M A Parisi, L S Finn, M Gunay-Aygun, M Al-Mateen, D Bates, C Clericuzio, H Demir, M Dorschner, A J van Essen, W A Gahl, M Gentile, N T Gorden, A Hikida, D Knutzen, H Ozyurek, I Phelps, P Rosenthal, A Verloes, H Weigand, P F Chance, W B Dobyns, I A Glass
Affiliations
Case Reports

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

D Doherty et al. J Med Genet. 2010 Jan.

Abstract

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.

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Figures

Figure 1
Figure 1
Liver biopsy findings in patients with COACH syndrome. (A) Ductal plate malformation, fetus with MKS: the portal triad with ductal plate malformation has a ring of irregularly shaped and dilated bile duct structures that parallel the limiting plate. Trichrome, 150×. (B) Normal liver, 4 years: the portal triad contains a bile duct (lower left lumen), hepatic artery (lower right lumen) and portal vein (upper lumen) within a minimal amount of supporting fibrocollagen. Trichrome, 300×. (C) UW65, 11 months: the portal triad is expanded by minimal fibrosis and too many duct profiles, located both at the limiting plate and within the connective tissue. Trichrome, 200×. (D) UW65, 9 years: the portal triad has moderate fibrosis and an excess of bile ducts and hepatic artery branches with only minimal inflammation. Trichrome, 200×. (E) UW49, 10 years: the explanted liver has dense portal fibrosis that extends between triads and focally forms nodules. Trichrome, 20×. (F) UW49, 10 years: a portal triad in the explant shows moderate fibrosis and several irregular bile duct profiles. Trichrome, 300×. (G) UW04-3, 5 years: the liver biopsy has intact lobular architecture with portal fibrosis and occasional septa bridging portal areas. Trichrome, 20×. (H) UW04-3, 5 years: a representative portal area shows several profiles of bile ducts and hepatic artery branches within dense fibrocollagen; central clear lumen is a normal portal vein branch. Trichrome, 300×.
Figure 2
Figure 2
Facial features, brain imaging and mutations for UW65 and UW49. (A) UW65 at 11 months of age. (B and C) Sagittal T1 weighted and axial T2 weighted brain magnetic resonance images demonstrating the molar tooth sign. (D) UW65 at 9 years of age. (E) MKS3 sequence tracings for UW65. (F) UW49 at 20 years of age. Photographs printed with permission from the families.
Figure 3
Figure 3
MKS3 mutations in COACH and Meckel syndromes. MKS3 encodes a 995 amino acid predicted protein with a signal peptide (sig), cysteine rich region, three transmembrane (TM) domains and a coiled-coil (CC) domain. Mutations identified in JSRD/COACH patients are listed above the protein diagram while mutations found in MKS patients are listed below. Previously unreported mutations are indicated with an asterix (*) and mutations also observed by Brancati et al are indicated with a plus sign (+).
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