Submission Details

The relationship between CDH15 variants and autosomal dominant intellectual disability (ID) was first suggested in 2008, when Bhalla et al. reported a balanced 11;16 chromosomal translocation disrupting two genes, CDH15 and KIRREL3, in a female patient with ID (PMID: 19012874). This translocation was not counted as evidence because the contribution of KIRREL3 cannot be ruled out. The authors also screened coding regions of these two genes in a cohort of patients with ID and identified four heterozygous missense variants in CDH15 (three with unknown inheritance and one inherited from an unaffected father). In vitro functional expression studies in mouse cells showed that three of the mutant proteins resulted in decreased cell adhesion. However, these four variants are observed in the gnomAD database at frequencies too high to be causative of disease and therefore were not scored as evidence. According to gnomAD (v2.1.1), CDH15 is not constrained for either loss-of-function or missense variants (pLI = 0, Z score = -1.01). Since then, two additional heterozygous CDH15 variants have been reported. In 2012, Bartnik et al. detected a 97 kb deletion containing CDH15 in a 9-month-old female with profound developmental delay, Rett-like syndrome, autistic features, and seizures. However, this deletion also included part of a neighboring gene, ACSF3, and was inherited from the healthy father (PMID: 22825934). In 2015, another heterozygous CDH15 missense variant was reported in a proband with speech delay, hyperactivity, and dysmorphic facial features, but this variant was also present in gnomAD and its inheritance and functional impact were unknown (PMID: 26077850). Therefore, no points were granted for genetic evidence regarding autosomal dominant ID. In addition, a homozygous splice variant in the last intron of CDH15 was reported in a 11-year-old female born to consanguineous parents with ID, hip dysplasia, prominent forehead, retrognathia, abnormal facial shape, and strabismus; no functional studies were performed (PMID: 28940097). The contribution of biallelic CDH15 variants to neurodevelopmental disorders is unknown, and is not addressed in this curation. Mouse model studies provide no supportive experimental evidence as homozygous CDH15 mutant mice were viable and fertile and did not show either gross developmental defects or abnormal cerebellum adherens junctions (PMID: 12052883). In summary, there is disputed evidence linking the CDH15 gene to autosomal dominant ID. This classification was approved by the ClinGen ID/Autism Gene Curation Expert Panel on 2/17/2021.