Early onset or syndromic epilepsy
Gene: CNKSR2Second case of a female presenting with seizures:
PMID: 31414730 - Polla et al 2019 - identified a novo variant, c.2304G>A (p.(Trp768*)), in the C-terminal protein coding part of the X-chromosomal gene CNKSR2 of a female child of a Dutch family who presented with seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities de novo variant. A mild skewing of X inactivation (20:80) was found in the blood of the patient.Created: 14 Aug 2022, 5:40 p.m. | Last Modified: 14 Aug 2022, 5:40 p.m.
Panel Version: 2.571
XL syndromic mental retardation - Houge type. Characterised by delayed development, ID, speech and lang delay and early onset seizures - some patients may have seizure remission in adolesecence. Vaags et al, 2014 - 3 adult brothers - delayed psychomotor development and seizures limited to childhood - hemizygous fs mutation identified - carried by unaff mum . Damiano et al, 2017 - family of AJ descent - variable manifestations - proband - most severely aff and onset of seizures at age 3.5 years. Brother had seizure onset at 3.5 years, sister seizure onset at 6 years and seizure free at 16. Mother had a history of febrile seizures and mothers brother had refractory seizures - hemi or het nonsense mutation identified. Cytogenetic deletions affecting the CNKSR2 gene have been reported - Houge et al, 2012, Vaags ewt al, 2015 & Aypar et al, 2015 - seizures reported in almost all aff.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Mental retardation, X-linked, syndromic, Houge type,301008
Publications
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on mode of inheritance: Updated mode of inheritance from XLR to XLD based on PMID:28098945, so that affected females are detected. Damiano et al., 2017 report the first female with a CNKSR2 variant and childhood epilepsy- the sister had a less severe phenotype than her two brothers, which could be subject to X-inactivation (not directly measured). The mother, who also carries the point mutation, had only febrile seizures.Created: 15 Jul 2019, 12:59 p.m. | Last Modified: 15 Jul 2019, 12:59 p.m.
Panel Version: 1.161
Gene originally listed on the Intellectual disability panel V2.42.
Associated with relevant phenotypes in OMIM and as probable Gen2Phen gene. At least 3 variants reported in unrelated cases.Created: 9 Apr 2018, 4:43 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes
Mental retardation, X-linked, syndromic, Houge type 301008
Publications
Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945; 34266427
Phenotypes for gene: CNKSR2 were changed from Mental retardation, X-linked, syndromic, Houge type 301008 to Intellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892; 25644381; 28098945
Source Wessex and West Midlands GLH was added to CNKSR2.
Source NHS GMS was added to CNKSR2.
Mode of inheritance for gene: CNKSR2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mode of inheritance for gene: CNKSR2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CNKSR2 were set to 28098945; 25223753; 22511892
Sarah Leigh: Gene originally listed on the
Victorian Clinical Genetics Services was added to CNKSR2. Panel: Genetic Epilepsy Syndromes
This gene has been classified as Green List (High Evidence).
CNKSR2 was added to Genetic Epilepsy Syndromes panel. Sources: Expert Review
CNKSR2 was created by Sarah Leigh