Genotype–phenotype correlation inCC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures

Abstract

CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.

Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause

“…A higher prevalence of ventriculomegaly has been reported in patients with CC2D2A -related JS compared with subjects without CC2D2A pathogenic variants 30. In our cohort, however, ventriculomegaly was associated with pathogenic variants in several genes.…”

“…In 13 patients with JS, we found a convex protuberance of the ventral contour of the midbrain; in four patients, a similar protuberance was seen at the dorsal contour of the lower medulla. These findings, not described in other disorders, were previously reported in single patients with JS 14 29 30. These protuberances are isointense to grey matter and have a nodular appearance.…”

“…When present, ventriculomegaly was mild in all patients. Hydrocephalus requiring shunting is rare in JS, reported in only five patients 30 44 45…”

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.…”

Mutations inTMEM231cause Joubert syndrome in French Canadians

“…The novel mutations c.4559A>G(p.Asn1520Ser) and c.4702T>C(p.Tyr1568His) are predicted to be damaging (by SIFT, Polyphen-2 and Mutation Taster) and neither variant has been reported in the Exome Variant Server (EVS; NHLBI GO Exome Sequencing Project), dbSNP135 or 1000 Genome datasets. These five CC2D2A mutations cluster in either the C2 domain (amino acids 1062–1174) or the C-terminal part of the protein, as do most missenses that cause JBTS 18. Segregation analysis revealed that all the affected individuals, but none of their unaffected relatives, were compound heterozygous for the mutations (see online supplementary figure S1).…”