Non-syndromic familial congenital anorectal malformations

Gene: CASK

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
FG syndrome

In OMIM and Gene2Phenotype CASK is associated with FG syndrome 4. OMIM reports that in affected members of an Italian family with FG syndrome-4 (300422), Piluso et al. (2009)(PMID: 19200522) identified a missense mutation (R28L) in the CASK gene that segregated fully with the disease and was not found in 1,000 ethnically matched control X chromosomes. The three affected males have many clinical signs of FG syndrome and marked mental retardation, relative macrocephaly, congenital hypotonia, behavioral disturbances, and severe constipation. The substitution is at a highly conserved residue in the CaM-kinase domain. Analysis of CASK protein functions as well as structural and dynamic studies did not reveal significant alterations induced by the p.R28L substitution although a partial skipping of the exon 2 of CASK was observed.

Dunn et al (2017)(PMID: 28139025) describes a patient with a de novo splice site mutation in CASK (c.2521-2A>G) and clinical features of the FG syndrome-4 including severe constipation.

Other reports of variants in the CASK gene and X-linked mental retardation with additional phenotypic features (e.g. Hackett et al., 2010 (PMID: 20029458), Moog et al., 2015 (PMID: 25886057) but they do not appear to show an anorectal associated phenotype. Burglen et al 2012(PMID: 22452838) report frequent constipation in 11 female patients with Pontocerebellar hypoplasia and CASK inactivating mutations.

Created: 8 Oct 2018, 9:35 p.m.

Comment on list classification: Rated gene Amber as is on expert list. Keeping Amber as only 2 reported cases/families with variants in CASK and FG syndrome 4 phenotype. Not certain that an anorectal malformation is the cause of the severe constipation seen.

Created: 19 Sep 2018, 4:20 p.m.

Gene added from expert list from Dr Charles Shaw-Smith (Royal Devon and Exeter NHS Foundation Trust) in relation to FG syndrome

Created: 19 Sep 2018, 4:19 p.m.