CDH15

protein-coding

cadherin 15, the group of Type I classical cadherins

Gene summary

This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]

Previous symbols:

CDH3
CDH14

MANE transcript

NM_004933.3

Inheritance

ClinVar variants

U:261B:131

Top phenotype

Intellectual developmental disorder, autosomal dominant 3

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr16:89,171,748-89,195,492

External References & Databases

Ensembl (ENSG00000129910)

Transcript & Mutation Effects

hg38 • Region Span ~23.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012946

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012946

Submitter: G2P

intellectual developmental disorder, autosomal dominant 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012946

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: ClinGen

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.

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 3AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19012874

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDH15 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 274

not providedTotal: 136

Intellectual disability, autosomal dominant 3Total: 35

CDH15-related disorderTotal: 24

Intellectual disabilityTotal: 8

von Willebrand disease type 1Total: 1

Neurofibromatosis, type 1Total: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004933.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	69 clinvar	4 clinvar	76
missense			246 clinvar	53 clinvar	5 clinvar	304
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	261	122	9	392

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004933.3	RefSeq	NP_004924.1	14	MANE Select
ENST00000289746.3	Ensembl	ENSP00000289746.2	14	MANE Select
ENST00000859655.1	Ensembl	ENSP00000529714.1	14	Standard
ENST00000859655.2	Ensembl	ENSP00000529714.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cdh15	Danio rerio	Structure: slow muscle cell Quality: elongated abnormal

Gene / Model

Organism

Observed Phenotype

cdh15

Danio rerio

Structure: slow muscle cell

Quality: elongated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cell adhesion molecules (CAMs) - Homo sapiens (human)
Developmental Biology
CDO in myogenesis
Myogenesis
Cell-cell junction organization

Biological Process

cell morphogenesis
cell-cell junction assembly
cell adhesion
homophilic cell adhesion via plasma membrane adhesion molecules
calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules

Molecular Function

calcium ion binding
protein binding
cytoskeletal protein binding
protein homodimerization activity
cadherin binding

Cellular Component

Golgi apparatus
cytosol
plasma membrane
caveola
cell-cell adherens junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000289746
Coding exons: 14
Length: 23726
Individuals with no LoFs: 125485
Homozygous LoFs: 0
Heterozygous LoFs: 179
Defined: 125664
p: 0.000712

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.01	591	526	1.12	0.0000342	5153
Missense (PolyPhen)		206	203.33	1.0131		2052
Synonymous	-2.20	294	250	1.18	0.0000179	1764
Loss of Function	1.09	25	31.6	0.791	0.00000150	321

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.0032	0.0032	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00079	0.00076	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00032	0.00030	rare
South Asian	0.00033	0.00033	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. M-cadherin is part of the myogenic program and may provide a trigger for terminal muscle differentiation.;
Disease: DISEASE: Note=A chromosomal aberration involving CDH15 and KIRREL3 is found in a patient with severe mental retardation and dysmorphic facial features. Translocation t(11;16)(q24.2;q24).; DISEASE: Mental retardation, autosomal dominant 3 (MRD3) [MIM:612580]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:19012874}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.663
RVIS EVS: -1.08
RVIS percentile EVS: 7.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.830

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium