Missense variants in TMEM67 in a patient with Joubert syndrome.

We present a patient with hypotonia, developmental delays, hepatomegaly, low platelet counts, and ocular colobomas, consistent with Joubert syndrome with COACH phenotype. She carries two variants in TMEM67. Reclassification in light of clinical information suggests pathogenicity of the c.517T>C (p.Cys173Arg) variant. Early MRI imaging missed a molar tooth sign. Joubert syndrome (JS) is an autosomal recessive disorder characterized by a cerebellar and brainstem malformation called the “molar tooth sign,” hypotonia with eventual ataxia and developmental delays.1 The molar tooth sign involves hypoplasia of the cerebellar vermis, thick superior cerebellar peduncles, and a particularly deep interpeduncular fossa and is mandatory in the diagnosis of Joubert syndrome.2 Joubert syndrome is one of six subgroups of phenotypes that all present with the molar tooth sign. All six are classified in Joubert syndrome and related disorders (JSRD) group: (a) pure JS, (b) JS with ocular defect, (c) JS with renal defect, (d) JS with oculorenal defects, (e) JS with hepatic defect, and (f) JS with orofaciodigital defects.3 Although the true prevalence of JSRD is unknown, estimates range from 1:80 000 to 1:100 000.3, 4 The clinical heterogeneity of JSRD is reflected in significant genetic heterogeneity with some genotype‐phenotype correlations. Biallelic pathogenic variants have been identified in approximately 50% of patients with JSRD. Thirty‐four genes have been identified in the pathogenesis; alterations in the following genes are most commonly found: AHI1, CPLANE1, CC2D2A, CEP290, CSPP1, INPP5E, KIAA0586, MKS1, NPHP1, RPGRIP1L, TCTN2, TMEM67, and TMEM216.5 JSRD are ciliopathies as these genes encode ciliary structural and regulatory proteins. Joubert syndrome with hepatic defect is also known as COACH syndrome: Cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis.6 Mutations in TMEM67 (MKS3) are responsible for the majority of COACH syndrome, although mutations in CC2D2A and RPGRIP1L can also be causative.7 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 To evaluate pathogenicity of variants, laboratories rely on the current literature, functional validation and databases, and computational (in silico) predictive programs.13 However, as these variants may have been previously unseen or insufficient data have been collected on them, the absence of information results in variants being interpreted as neither benign nor pathogenic, but of unknown significance. Clinical correlation also contributes to variant classification, which can be difficult for the testing laboratory to obtain or to interpret. As genetic testing becomes more accessible, it is likely that more variants of unknown significance (VUS) will surface, requiring classification. Here, we present a patient without a family history of Joubert syndrome who carries two heterozygous variants, classified by the testing laboratory as variants of uncertain significance, in TMEM67: c517T>C (p.Cys173Arg) and c.934T>C (p.Ser312Pro) and the following clinical findings: molar tooth sign, hypotonia, developmental delays, hepatomegaly, low platelet counts, and ocular colobomas, consistent with Joubert syndrome with the COACH phenotype.