ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
25106414 Asadollahi et al (2014) claimed to be the first to associate haploinsufficiency of CTNND2 with borderline low IQ with or without autistic features or developmental delay. They reported on an 11 y.o. female with a de novo 113 kb deletion of exons 4-7 at chr5:11,431,816-11,545,236 who had borderline intellectual disability (full-scale IQ 77), learning difficulties, short attention, social-emotional issues, and mild facial dysmorphism.
25807484 Turner et al (2015) summarized findings from the literature, from the clinical cytogenetics laboratories at Emory University and Baylor College of Medicine, and from the Autism Genetic Resource Exchange (AGRE). From these sources, they reported on 12 CNVs (ten deletions and two duplications) in CTNND2. 7 of the listed deletions were focal deletions within CTNND2. Parental origin of the 7 focal deletions was varied: 1 was de novo, 3 were maternal, 1 was paternal, and 2 were not reported. No clinical information was provided for the parents who carried these deletions. This incidence of loss-of-function mutations in neurodevelopmental disorders was found to be significantly increased compared to independent cases referred for other indications. In vivo functional studies of CTNND2 in zebrafish demonstrate that CTNND2 plays a critical role in the formation and/or maintenance of synapses.
25473103 Hofmeister et al (2015) reported on a mother and daughter with complex rearrangements affecting CTNND2. Both individuals had borderline intelligence and learning problems. Karyotyping identified both to have two apparently balanced translocations t(1;8)(p22;q24) and t(5;18)(p15;q11). Whole-genome mate-pair sequencing and breakpoint PCR clarified the exact positions of the chromosomal breaks. The translocation breakpoint on chromosome 5 was narrowed down to chr5:11291109-11291112. This breakpoint occurs in exon 9 of CTNND2 leading to a loss-of-function mutation. Zebrafish studies involving knockdown of CTNND2 showed this affected neuronal migration. Patient 3 had a deletion of exons 12-18 (out of frame) in CTNND2 and was found to have mild intellectual disability as well as dysmorphism. His unaffected mother was reportedly mosaic for the microdeletion based upon segregation analysis from qPCR. Belcaro et al (2015, PMID 25839933) reported on two patients with isolated intellectual disability and focal deletions in CTNND2. Patient 1 had a 39 kb intronic deletion at chr5:11,422,171-11,461,920. Patient 2 had a 27.6 kb deletion involving exon 14 at chr5:11,322,037-11,349,674. The patient inherited this deletion from his mother who reportedly walked late, but otherwise had no other reported delays. While more recent evidence is suggesting that this gene is involved in neurodevelopmental phenotypes, given the non-specific phenotype and the number of inherited deletions, the current haploinsuficiency score for CTNND2 is a 2.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.