Non-syndromic familial congenital anorectal malformations
Gene: CASK
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 syndromeCreated: 19 Sep 2018, 4:19 p.m.
Eleanor Williams: Gene added from expert list fr
Publications for gene: CASK were set to 19200522; 28139025; 20029458; 25886057
Tag watchlist tag was added to gene: CASK.
Gene: cask has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: CASK was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CASK were set to
Phenotypes for gene: CASK were changed from anorectal malformation to anorectal malformation; FG syndrome 4 300422
Gene: cask has been classified as Amber List (Moderate Evidence).
Gene: cask has been classified as Red List (Low Evidence).
Added phenotypes anorectal malformation for gene: CASK
gene: CASK was added gene: CASK was added to Non-syndromic familial congenital anorectal malformations. Sources: Expert list Mode of inheritance for gene: CASK was set to Phenotypes for gene: CASK were set to anorectal malformation