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Intellectual disability - microarray and sequencing v3.1758 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to
Intellectual disability - microarray and sequencing v3.1757 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Mental retardation, autosomal dominant 19, 615075Colorectal cancer, somatic, 114500Pilomatricoma, somatic, 132600Ovarian cancer, somatic, 167000Hepatocellular carcinoma, somatic, 114550; MENTAL RETARDATION, AUTOSOMAL DOMINANT 19 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Intellectual disability - microarray and sequencing v2.1047 CSDE1 Konstantinos Varvagiannis gene: CSDE1 was added
gene: CSDE1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CSDE1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Phenotypes for gene: CSDE1 were set to Autism; Global developmental delay; Intellectual disability
Penetrance for gene: CSDE1 were set to unknown
Review for gene: CSDE1 was set to GREEN
Added comment: Guo et al. (2019 - DOI: 10.1126/sciadv.aax2166) report on 18 individuals from 18 unrelated families, with heterozygous likely gene disrupting (stopgain/frameshift/spice-site) CSDE1 variants.

Initial sequencing with MIPs found in 3 individuals from an autism cohort (4045 probands), while subsequent targeted sequencing of a larger cohort (autism spectrum/ID network) led to identification of 5 additional relevant individuals and Genematcher/collaborations a further 10 (the latter by WES).

Consistent phenotypes included ASD (10 of 15 formally evaluated), DD (motor: 15/17 - speech: 17/17) and ID (mild to severe in 14 of 16 assessed, in further 2 in the below-average range). Recurrent seizures or epilepsy were reported for 7 of 16 patients. Other variable features were anxiety or ADHD, increased OFC, ocular, hand and MRI anomalies.

The study was mainly focused on LGD variants with p.R123* (NM_001242891.1:c.367C>T) being a reccurrent one, found in 3 families.

8 of these variants were de novo, 8 further inherited (often from a less severely affected parent, although parental neuropsychiatric status was not available for individuals from all 3 groups). In 2 cases inheritance was unknown (only 1 parental sample available).

3 individuals with de novo missense variants were also identified. Features in those individuals also included ASD and/or DD and ID (2/3) [Table S1].

Arguments to support involvement of the CSDE1 variants included the:
- role of the gene encoding an RNA binding protein implicated in neuronal migration/differentiation (cited : 24012837, 29129916),
- statistically significant burden of the variants in the cohorts examined,
- relevant CSDE1 intolerance scores (pLI of 1 and %RVIS of 6.18),
- relevant human (mRNA) / mouse (protein) spatial and temporal expression patterns,
- exclusion of apparent alternative diagnoses to the extent possible in many subjects with CNVs/SNVs/ROH of uncertain significance in very few,
- cosegregation with rather similar neuropsychiatric phenotypes in case of carrier parents,
- enrichment of ASD-related genes (and FMRP targets) among CSDE1-binding targets,
- suppression of Ctnnb1 expression (at the protein level) affecting Wnt/β-catenin signalling,
- effect of knockdown and/or mutants in mouse (shRNA) and Drosophila (mt and siRNA) models affecting synapse formation and synaptic transmission,
- rescue of many of the previous phenotypes by expression of human CSDE1 (mice), expression of stabilized β-Catenin (mice) or RNAi-stable-dUNR (Drosophila) [also supporting LoF as the underlying effect of variants].

CSDE1 is not commonly included in gene panels for ID offered by diagnostic laboratories. There is no associated phenotype in OMIM/G2P.

Overall, this gene could be considered for inclusion in the ID panel probably as green (or amber).
Sources: Literature
Intellectual disability - microarray and sequencing v2.468 CTNNB1 Louise Daugherty Source Victorian Clinical Genetics Services was added to CTNNB1.
Intellectual disability - microarray and sequencing CTNNB1 BRIDGE consortium edited their review of CTNNB1
Intellectual disability - microarray and sequencing CTNNB1 BRIDGE consortium edited their review of CTNNB1
Intellectual disability - microarray and sequencing CTNNB1 BRIDGE consortium reviewed CTNNB1