Intellectual disability syndromic and non-syndromic
Gene: CTNND2 Amber List (moderate evidence)Green List (high evidence)
Additional cases:
PMID: 38604781 - heterozygous and homozygous loss of function microdeletion encompassing the last 19 exons of CTNND2 in consanguineous family. Three siblings with homozygous deletion have severe NDD including absent speech, profound motor delay, stereotypical behaviour and other. Heterozygous carriers (sibling and parents) showed milder NDD phenotype similar to previously reported heterozygous cases.
PMID: 25473103 - mother and daughter with borderline intelligence, learning problems and dyslexia carry balanced reciprocal translocations: t(1;8) (p22;q24) and t(5;18)(p15;q11). No genes were affected at breakpoints on chromosomes 1 and 8. The t(5;18) showed a breakpoint in intron 9 of CTNND2, while the chromosome 18 breakpoint was in a gene without morbid associations. The genes run in opposite directions and the fusion genes are predicted to cause loss of function. Third case with out of frame deletion exon 12-18 has mild intellectual disability, reading difficulties and facial features. The deletion is present in the mother in mosaic form.
PMID: 31814264 – de novo 97kb duplication, containing exon 3 of CTNND2, which is out of frame and predicted to undergo NMD, and was shown to be in tandem. The individual has developmental delay, behavioural problems and dysmorphic features. Secondary deletion on 5q14.1 deemed not pathogenic as present in mother and sibling without matching features. No functional studies available.
Not sure on biallelic/AR as single family with AR inheritance is consanguineous (although tested by exomes using ID gene panel). AD NDD/ID seems to have a loss of function mechanism and variable expressivity.Created: 9 Dec 2025, 12:45 p.m. | Last Modified: 9 Dec 2025, 12:50 p.m.
Panel Version: 1.491
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Neurodevelopmental disorders (NDDs), intellectual disability (ID), autism, behavioural issues
Publications
I don't know
Comment when marking as ready: Additional cytogenetic evidence noted. However, causality not established by these observations, maintain Amber rating.Created: 15 Dec 2025, 10:35 a.m. | Last Modified: 15 Dec 2025, 10:35 a.m.
Panel Version: 1.497
Two individuals with intragenic deletions. One family with missense variant and epilepsy. Association with autism in a large cohort and zebrafish model.Created: 17 Jan 2020, 4:38 p.m. | Last Modified: 17 Jan 2020, 4:38 p.m.
Panel Version: 0.1615
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability; Autism; Epilepsy
Publications
Gene: ctnnd2 has been classified as Amber List (Moderate Evidence).
Publications for gene: CTNND2 were set to 25839933; 29127138; 25807484
Phenotypes for gene: CTNND2 were changed from Intellectual disability; Autism; Epilepsy to Neurodevelopmental disorder, MONDO:0700092, CTNND2-related
Gene: ctnnd2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CTNND2 were changed from Intellectual disability; Autism; Epilepsy to Intellectual disability; Autism; Epilepsy
Mode of inheritance for gene: CTNND2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CTNND2 were changed from to Intellectual disability; Autism; Epilepsy
Publications for gene: CTNND2 were set to
Gene: ctnnd2 has been classified as Amber List (Moderate Evidence).
gene: CTNND2 was added gene: CTNND2 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: CTNND2 was set to Unknown
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 panelapp@genomicsengland.co.uk
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.