Intellectual disability - microarray and sequencing
Gene: CTNND2 Red List (low evidence)This gene is not associated with any phenotype in OMIM but is linked to 'CTNND2-related neurodevelopmental disorder' in Gene2Phenotype with a 'strong' disease confidence category.
CTNND2 maps to a critical region on chromosome 5p15.2 that is deleted in cri-du-chat syndrome. Both structural and single nucleotide variants have also been associated with various other neurodevelopmental phenotypes including ASD, ADHD, depression, cerebral palsy, anxiety, epilepsy, and schizophrenia.
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Specifically relating to ID:
PMID:10673328 (2000), PMID: 24677774 (2014) - breakpoints in patients with 5p terminal deletions have been characterised with respect to symptom severity and the deletion size/location. This revealed a correlation between hemizygous loss of CTNND2, in particular, and severe mental impairment.
PMID: 25839933 (2015) - Two unrelated individuals with intragenic CTNND2 deletions and isolated mild intellectual disability. In one case the variant was maternally inherited, where the mother also had delayed psychomotor development milestones, but otherwise no ID.
PMID: 29127138 (2017) - Three patients in one family with familial cortical myoclonic tremor and epilepsy were found to harbour with a missense variant (p.Glu1044Lys) in the CTNND2 gene that co-segregated with the phenotype.
PMID: 25473103 (2015) - Intragenic deletion affecting exons 12–18 of the CTNND2 gene identified in a patient with pronounced learning disabilities, dysmorphic features, joint laxity in the fingers and a marfanoid habitus.
PMID: 25106414 (2014) - Patient with a de novo 113 kb out-of-frame deletion encompassing exons 4–7 of CTNND2, presenting clinically with borderline ID and mild facial dysmorphic features.
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Mouse studies:
PMID: 15380068 (2004) - CTNND2 null mice display severe deficits in learning, memory, and synaptic plasticity.
PMID:19914181 (2009) - CTNND2 null mice show normal neuronal development and synaptic ultrastructure. However, after 5-weeks of age mutant mice experience progressive dendritic retraction, a reduction in spine density and stability, and concomitant reductions in cortical responsiveness, indicating that CTNND2 is required to maintain dendrites and dendritic spines in mature cortex, but not to establish these structures during development.Created: 26 Feb 2024, 4:37 p.m. | Last Modified: 26 Feb 2024, 4:37 p.m.
Panel Version: 5.465
Phenotypes for gene: CTNND2 were changed from to CTNND2-related neurodevelopmental disorder
Mode of inheritance for gene: CTNND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
gene: CTNND2 was added gene: CTNND2 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: CTNND2 was set to
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.