Intellectual disability - microarray and sequencing
Gene: CDH2
Four additional unrelated individuals reported in PMID: 31650526 (2020). Cognitive delays were a feature in 2/3.Created: 1 Dec 2020, 5:04 p.m. | Last Modified: 1 Dec 2020, 5:04 p.m.
Panel Version: 3.573
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929
Publications
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 9 variants reported in unrelated cases, ID was reported in four of the cases (2/8 mild and 2/8 moderate (PMID 31585109).
The "for-review" tag has been added to this gene as there is enough evidence for this gene to be rated RED at the next major review.Created: 22 Oct 2020, 5:12 p.m. | Last Modified: 22 Oct 2020, 5:12 p.m.
Panel Version: 3.483
Nine unrelated individuals with a neurodevelopmental/syndromic disorder and de novo variants in this gene. Although ID was a variable feature, you may want to consider including here as Green -- otherwise this gene-disease association is not covered by any of the paediatric rare disease panels as far as I can see.Created: 1 Feb 2020, 1:06 a.m. | Last Modified: 1 Feb 2020, 1:06 a.m.
Panel Version: 3.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability; corpus callosum abnormalities; congenital abnormalities
Publications
Variants in this GENE are reported as part of current diagnostic practice
CDH2 reviewd by Konstantinos Varvagiannis following a publication by Accogli et al. (2019 - PMID: 31585109) who reported on 9 individuals with de novo pathogenic CDH2 variants.
CDH2 is not in OMIM or Gene2Phenotype. There are >3 individuals/variants/families where ID is reported however it is not seen in all cases and in some cases is mild. Therefore classify CDH2 as Amber until more evidence is available.Created: 24 Oct 2019, 2:49 p.m. | Last Modified: 24 Oct 2019, 2:49 p.m.
Panel Version: 2.1079
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.
Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).
CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).
Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).
Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.
One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .
Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.
Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.
Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
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The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
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As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: LiteratureCreated: 6 Oct 2019, 6:31 p.m. | Last Modified: 6 Oct 2019, 6:36 p.m.
Panel Version: 2.1062
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability
Publications
Tag for-review was removed from gene: CDH2.
Source Expert Review Green was added to CDH2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were changed from Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929
Tag for-review tag was added to gene: CDH2.
Gene: cdh2 has been classified as Amber List (Moderate Evidence).
gene: CDH2 was added gene: CDH2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDH2 were set to 31585109; 9015265; 17222817 Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability Penetrance for gene: CDH2 were set to unknown Review for gene: CDH2 was set to AMBER