CDH23

protein-coding

cadherin related 23, the group of Cadherin related|MicroRNA protein coding host genes

Gene summary

This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

Previous symbols:

DFNB12
USH1D

MANE transcript

NM_022124.6

Inheritance

AR, AD, Digenic

ClinVar variants

P:810U:2095B:1922

Top phenotype

Pituitary adenoma 5, multiple types; Deafness, autosomal recessive 12; Usher syndrome, type 1D; Usher syndrome, type 1D /F digenic

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr10:71,396,920-71,815,947

External References & Databases

Ensembl (ENSG00000107736)

Transcript & Mutation Effects

hg38 • Region Span ~419.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between CDH23 and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 11/30/2017. Variants in CDH23 were first reported in humans with this disease as early as 2007 (Wagatsuma et al. 2007). At least 23 missense and 1 in-frame deletion have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 40 probands in 4 publications (17850630, 19888295, 22899989, 21940737). Variants in this gene segregated with disease in 9 additional family members. Only 9 missense variants have been scored in 9 probands, because the individuals were tested by funduscopy which sufficiently ruled out retinitis pigmentosa (Schultz et al. 2011, 21940737). Of note, this gene has also been implicated in Usher syndrome Type 1. Mostly loss of function variants in CDH23 have been associated with Usher syndrome Type 1, therefore this has been assessed separately as Definitive by the ClinGen Hearing Loss Working Group. The CDH23 and autosomal recessive nonsyndromic hearing loss gene-disease association is supported by multiple mouse models, including models with spontaneous homozygous missense variants (19270079, 27882946, 25732708, 21689626). Expression analysis suggests apoptosis as a mechanism of disease. In summary, CDH23 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 5/22/2018.

Usher syndrome type 1DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010984

Submitter: G2P

Usher syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: Orphanet

pituitary adenoma 5, multiple typesLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0054601

Submitter: Natera

autosomal recessive nonsyndromic hearing loss 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011067

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 1DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010984

Submitter: Natera

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Usher syndrome type 1DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010984

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 12DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011067

Submitter: G2P

Clinical Genomic Database (CGD)

Pituitary adenoma 5, multiple types; Deafness, autosomal recessive 12; Usher syndrome, type 1D; Usher syndrome, type 1D /F digenicAD/AR/Digenic

Manifestation: Audiologic/Otolaryngologic; Oncologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Oncologic

Rationale: For Pituitary adenoma, multiple types, awareness may allow early diagnosis and management of pituitary neoplasms; For Deafness and Usher syndrome, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Inheritance of Usher syndrome can be digenic, involving PCDH15

Refs: 11138009; 11090341; 11138008; 15537665; 17850630; 28413019

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDH23 variants in ClinVar

43 Conditions Cataloged

not providedTotal: 5230

Usher syndrome type 1Total: 1063

not specifiedTotal: 976

Autosomal recessive nonsyndromic hearing loss 12Total: 698

CDH23-related disorderTotal: 686

Usher syndrome type 1DTotal: 606

Inborn genetic diseasesTotal: 549

Pituitary adenoma 5, multiple typesTotal: 418

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022124.6. 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	2 clinvar	2 clinvar	71 clinvar	1755 clinvar	22 clinvar	1852
missense	15 clinvar	111 clinvar	2000 clinvar	134 clinvar	11 clinvar	2271
nonsense	65 clinvar	71 clinvar	1 clinvar			137
start loss			1 clinvar			1
frameshift	169 clinvar	172 clinvar	14 clinvar			355
splice donor/acceptor (+/-2bp)	38 clinvar	165 clinvar	8 clinvar			211
Total	289	521	2095	1889	33	4827

Highest pathogenic variant AF is 0.00017631473

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022124.6	RefSeq	NP_071407.4	69	MANE Select
ENST00000224721.12	Ensembl	ENSP00000224721.9	69	MANE Select
NM_001171930.2	RefSeq	NP_001165401.1	31	Standard
NM_001171931.2	RefSeq	NP_001165402.1	25	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cdh23	Danio rerio	Structure: neuromast hair cell Quality: physical object quality abnormal

Gene / Model

Organism

Observed Phenotype

cdh23

Danio rerio

Structure: neuromast hair cell

Quality: physical object quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

calcium ion transport
homophilic cell adhesion via plasma membrane adhesion molecules
visual perception
sensory perception of sound
locomotory behavior

Molecular Function

calcium ion binding
protein binding

Cellular Component

plasma membrane
membrane
integral component of membrane
stereocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398788
Coding exons: 22
Length: 419012
Individuals with no LoFs: 124661
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 124697
p: 0.000144

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.707	662	715	0.926	0.0000471	7218
Missense (PolyPhen)		116	141.92	0.81739		1424
Synonymous	0.510	290	301	0.963	0.0000209	2270
Loss of Function	3.93	18	47.1	0.382	0.00000231	521

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00016	0.00016	rare
Other	0.00018	0.00016	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. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing. {ECO:0000269|PubMed:11138009, ECO:0000269|PubMed:16679490}.;
Disease: DISEASE: Usher syndrome 1D (USH1D) [MIM:601067]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. {ECO:0000269|PubMed:11138009, ECO:0000269|PubMed:12075507, ECO:0000269|PubMed:15660226, ECO:0000269|PubMed:16679490, ECO:0000269|PubMed:18429043}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Usher syndrome 1D/F (USH1DF) [MIM:601067]: USH1DF patients are heterozygous for mutations in CDH23 and PCDH15, indicating a digenic inheritance pattern. {ECO:0000269|PubMed:15537665}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 12 (DFNB12) [MIM:601386]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:11090341, ECO:0000269|PubMed:12075507, ECO:0000269|PubMed:12522556, ECO:0000269|PubMed:15829536, ECO:0000269|PubMed:16679490, ECO:0000269|PubMed:17850630, ECO:0000269|PubMed:22899989, ECO:0000269|PubMed:24767429}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pituitary adenoma 5, multiple types (PITA5) [MIM:617540]: A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete: growth hormone (GH)-secreting, prolactin (PRL)-secreting, adrenocorticotropin (ACTH)-secreting, thyroid- stimulating hormone (TSH)-secreting, and plurihormonal (GH and TSH) tumors. Familial and sporadic forms have been reported. The transmission pattern of familial PITA5 is consistent with autosomal dominant inheritance with reduced penetrance. {ECO:0000269|PubMed:28413019}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.203

Intolerance Scores

LoFtool: 0.591
RVIS EVS: -1.84
RVIS percentile EVS: 2.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.817

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High