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

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.

Missense variants in TMEM67 in a patient with Joubert syndrome

“…Mutations in similar regions in TMEM67 have been found in patients with Joubert syndrome and Joubert syndrome with the COACH (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis) phenotype. One patient with the COACH phenotype was found to carry a missense mutation at nucleotide position 515, with a G to A substitution (c.515G>A (p.Arg172Gln)) 7. These are all consistent with this variant meeting ACMG PM1 criteria 13.…”

“…TMEM67/MKS3 is found on chromosome 8 (8q22.1) and encodes a 955‐amino acid seven‐transmembrane receptor protein that is thought to regulate cilia function and mutations in TMEM67/MKS3 can also cause Meckel‐Gruber syndrome (MKS), another autosomal recessive ciliopathy that is associated with renal cystic disease 8, 9, 10, 11. Although mutations in TMEM67/MKS3 are causative for both syndromes (accounting for 9% of JSRD cases and 16% of MKS cases), a correlation between missense mutations in exons 8‐15, particularly in combination with truncating mutations, and Meckel‐Gruber syndrome has been identified 7, 12…”

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…2 It is estimated that known genes overall account for about half of cases, suggesting further genetic heterogeneity; moreover, genotype-phenotype correlates have been clearly established only for few JSRD-causative genes. [5][6][7][8][9] In 2009, Jacoby et al 10 identified INPP5E mutations in a family with MORM syndrome, a rare autosomal recessive condition related to Bardet-Biedl syndrome. In the same year, we identified homozygous INPP5E mutations in seven consanguineous families genetically linked to the first JSRD locus (JBTS1) on 9q34.…”

Retinal Abnormalities Characteristic of Inherited Renal Disease

“…41 Mutations affect one of the MKS3, CC2D2A, or RPGRIP1L genes. 42 MSK3 mutations account for nearly 60% of cases. 43 Patients may have the molar tooth sign, a midbrain-hindbrain malformation also seen in Joubert syndrome and congenital hepatic fibrosis.…”