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Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)
  1. D Doherty1,
  2. M A Parisi2,
  3. L S Finn3,
  4. M Gunay-Aygun2,
  5. M Al-Mateen4,
  6. D Bates3,
  7. C Clericuzio5,
  8. H Demir6,
  9. M Dorschner3,
  10. A J van Essen7,
  11. W A Gahl2,
  12. M Gentile8,
  13. N T Gorden3,
  14. A Hikida3,
  15. D Knutzen3,
  16. H Özyurek9,
  17. I Phelps3,
  18. P Rosenthal10,
  19. A Verloes11,
  20. H Weigand12,
  21. P F Chance3,
  22. W B Dobyns13,
  23. I A Glass3
  1. 1University of Washington, Seattle, Washington, USA
  2. 2National Institutes of Health, Bethesda, Maryland, USA
  3. 3University of Washington, Seattle, Washington, USA
  4. 4Mary Bridge Pediatric Neurology, Tacoma, Washington, USA
  5. 5University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
  6. 6Hacettepe University, Ankara, Turkey
  7. 7University of Groningen, Groningen, The Netherlands
  8. 8IRCCS de Bellis Hospital, Castellana Grotte, Italy
  9. 9Ondokuz Mayis University, Samsun, Turkey
  10. 10University of California, San Francisco, San Francisco, California, USA
  11. 11Hopital Robert DEBRE, Paris, France
  12. 12University of Munich, Munich, Germany
  13. 13University of Chicago, Chicago, Illinois, USA
  1. Correspondence to Dr D Doherty, University of Washington Box 356320, 1959 NE Pacific St, Seattle, WA 98195-0320, USA; ddoher{at}


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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  • DD and MAP contributed equally

  • Funding This work was supported by the US National Institutes of Health (grants K23NS45832 to MAP, K24HD46712 to IAG, NCRR 5KL2RR025015 to DD, R01NS050375 to WBD), the March of Dimes Endowment for Healthier Babies (DD, MAP, and IAG), the Ames Endowment Fund at Seattle Children's Hospital (IAG), and the Allan and Phyllis Treuer Endowed Chair (PFC) at Seattle Children's Hospital.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and Peer review Not commissioned; externally peer reviewed.