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CADHERIN 23; CDH23

CADHERIN 23; CDH23

Alternative titles; symbolsOTOCADHERINCADHERIN-RELATED FAMILY, MEMBER 23; CDHR23HGNC Approved Gene Symbol: CDH23Cytogenetic location: 10q22.1 Genomic coordin...

Alternative titles; symbols

  • OTOCADHERIN
  • CADHERIN-RELATED FAMILY, MEMBER 23; CDHR23

HGNC Approved Gene Symbol: CDH23

Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:71,396,919-71,815,946 (from NCBI)

▼ Description
The CDH23 gene encodes a member of the cadherin superfamily, which comprises calcium-dependent cell-cell adhesion glycoproteins (summary by Zhang et al., 2017).

▼ Cloning and Expression
Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier of deaf waddler (mdfw), and age-related hearing loss (Ahl). The orthologous human chromosomal region is 10q21-q22, which contains the human deafness loci DFNB12 (601386) and USH1D (601067). Di Palma et al. (2001) identified the Cdh23 gene as that mutated in waltzer mice. The 10.5-kb Cdh23 cDNA encodes a large, single-pass transmembrane protein that Di Palma et al. (2001) referred to as otocadherin. Cdh23 has an extracellular domain containing 27 repeats that show significant homology to the cadherin ectodomain.

Bolz et al. (2001) found that the CDH23 gene encodes a predicted protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats.

▼ Gene Structure
The CDH23 gene contains 69 exons (Wagatsuma et al., 2007).

▼ Gene Function
Siemens et al. (2002) showed that CDH23 and harmonin (605242), another protein that is the site of mutations causing Usher syndrome, form a protein complex. Two PDZ domains in harmonin interact with 2 complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not in the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because Cdh23-deficient mice have splayed stereocilia, Siemens et al. (2002) suggested that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle, and that defects in the formation of this complex may disrupt stereocilia bundles and cause deafness in patients with Usher syndrome type I.

Boeda et al. (2002) noted that 3 distinct genetic forms of Usher syndrome are caused by defects in the CDH23, harmonin, and MYO7A (276903) genes. They observed severely disorganized hair bundles in shaker-1 mice, which carry a mutation in the Myo7a gene. Immunohistochemical analysis of differentiating hair cells indicated that Cdh23 was distributed normally, but harmonin b was not. Using human and mouse cDNA constructs and cells, they confirmed interaction between harmonin and CDH23 in vitro and in vivo. They also provided evidence that harmonin b anchors CDH23 to the stereocilia microfilaments and interacts directly with MYO7A, which conveys harmonin b along the actin core of the developing stereocilia. Boeda et al. (2002) proposed that the shaping of the hair bundle relies on a functional unit composed of MYO7A, harmonin b, and CDH23 and that the interaction of these proteins ensures the cohesion of the stereocilia.

Hawkins and Lovett (2004) reviewed the developmental genetics of auditory hair cells.

Kazmierczak et al. (2007) demonstrated that CDH23 and PCDH15 (605514), 2 cadherins that are linked to inherited forms of deafness in humans, interact to form tip links, extracellular filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel. Immunohistochemical studies using rodent hair cells showed that CDH23 and PCDH15 localized to the upper and lower part of tip links, respectively. The amino termini of the 2 cadherins colocalized on tip link filaments. Biochemical experiments showed that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. Ions that affected tip link integrity and a mutation in PCDH15 that causes a recessive form of deafness (see DFNB23, 609533) disrupted interactions between CDH23 and PCDH15. Kazmierczak et al. (2007) concluded that their studies defined the molecular composition of tip links and provided a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.

Using molecular dynamic simulations, Sotomayor et al. (2010) found that the first 2 extracellular cadherin (EC) repeats of mouse Cdh23 were relatively stiff and required binding of 3 Ca(2+) ions at the linker region for mechanical integrity. Sotomayor et al. (2010) predicted that mutations in CDH23 that alter Ca(2+) binding could affect bending between the EC repeats, particularly at lower Ca(2+) concentrations, and alter the function of the stereocilia tip links. They proposed that lack of vestibular phenotypes in some Cdh23 mutant mice and DFNB12 patients may be due to the higher Ca(2+) concentration in vestibular endolymph compared with cochlear endolymph.

Bahloul et al. (2010) found that isoforms of mouse Cdh23 that either included or excluded an exon 68-encoded sequence bound directly to the harmonin A isoform and to the tail of myosin-7a. The 3 proteins formed a complex that interacted with phosphatidylinositol 4,5-bisphosphate in synthetic liposomes.

▼ Biochemical Features
Crystal Structure

Sotomayor et al. (2012) combined crystallography, molecular dynamics simulations, and binding experiments to characterize the protocadherin-15 (605514)-cadherin-23 bond. They found a unique cadherin interaction mechanism in which the 2 most N-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predicted that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex was shown to become unstable in response to calcium removal owing to increased flexure of calcium-free cadherin repeats. Finally, Sotomayor et al. (2012) used structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function.

▼ Molecular Genetics
Usher Syndrome Type ID

Bolz et al. (2001) identified a Cuban pedigree in which type I Usher syndrome was linked to the USH1D locus on chromosome 10 (see 601067). Affected individuals presented with congenital deafness and a highly variable degree of retinal degeneration as an autosomal recessive trait. Using a positional candidate approach, Bolz et al. (2001) identified CDH23 as the gene responsible for USH1D in these individuals. In the Cuban family, the authors detected 2 different CDH23 mutations. A severe course of the retinal disease was observed in individuals homozygous for a presumed truncating splice site mutation (605516.0001), whereas mild retinitis pigmentosa was present in individuals carrying a homozygous missense mutation (605516.0002). Variable expression of the retinal phenotype was seen in patients with a combination of the 2 mutations. Bolz et al. (2001) also identified 2 mutations in the CDH23 gene in a German patient with Usher syndrome (605516.0003-605516.0004).

Simultaneously and independently, Bork et al. (2001) identified 2 nonsense and 2 frameshift mutations in the CDH23 gene (see, e.g., 605516.0007) in 4 families with USH1D.

In 33 patients with type I Usher syndrome in whom USH1B (276903) and USH1C (605242) had been excluded, von Brederlow et al. (2002) performed mutation screening by single-strand conformation polymorphism (SSCP) analysis and direct sequencing. On 8 disease alleles of 4 patients, 4 different mutations in the CDH23 gene were identified, 3 of them being novel. Among a total of 52 type I Usher cases studied by this group, CDH23 mutations accounted for about 10% of all disease alleles.

Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. Astuto et al. (2002) screened a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness for the presence of mutations in the entire coding region of CDH23, by heteroduplex, SSCP, and direct sequence analyses. Thirty-six different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. Seven mutations were common to more than 1 family. Ophthalmologic examination of patients with nonsyndromic deafness revealed asymptomatic manifestations similar to retinitis pigmentosa (RP; 268000), which indicated that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 displayed a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. Astuto et al. (2002) also presented a comprehensive catalog of CDH23 mutations identified both in their study and in patients reported elsewhere with either recessive nonsyndromic deafness or Usher syndrome type I.

Autosomal Recessive Deafness 12

In 5 families segregating autosomal recessive nonsyndromic hearing loss (DFNB12; 601386), Bork et al. (2001) identified 6 missense mutations in the CDH23 gene (see, e.g., 605516.0005-605516.0006).

In 5 sibs, born of consanguineous parents, with autosomal recessive deafness, Schultz et al. (2005) identified a homozygous phe1888-to-ser substitution in the CDH23 gene (F1888S; 605516.0010). Two of the sibs had high frequency hearing loss and 3 had severe to profound hearing loss affecting all frequencies. The 3 severely affected sibs were additionally heterozygous for a val586-to-met substitution in the ATP2B2 gene (V586M; 108733.0001).

Wagatsuma et al. (2007) identified homozygosity or compound heterozygosity for 4 different missense mutations in the CDH23 gene (see, e.g., 605516.0014 and 605516.0015) in 6 Japanese patients from 5 families with autosomal recessive hearing loss. All four mutations were in the extracellular domain of the protein. The findings indicated that mutations in the CDH23 gene may account for about 5% of nonsyndromic hearing loss in the Japanese population.

Usher Syndrome Type ID/F

Zheng et al. (2005) reported 3 families with Usher syndrome type I in which affected members carried mutations in both CDH23 and PCDH15 (605514), thus supporting a digenic model for some individuals with this phenotype. Based on an animal model, the authors concluded that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.

Pituitary Adenoma 5, Susceptibility to

In affected members of 4 unrelated families with both functional GH-secreting and nonfunctional pituitary adenomas (PITA5; 617540), Zhang et al. (2017) identified germline heterozygous missense mutations in the CDH23 gene (605516.0016-605516.0019). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was evidence of age-dependent or incomplete penetrance. Whole-exome sequencing of 125 individuals with sporadic pituitary adenomas identified CDH23 mutations in 15 individuals (12.0%); 13 had heterozygous mutations and 2 had homozygous mutations. The tumor types in these patients varied. All mutations identified occurred at highly conserved residues in the EC domains of CDH23 and were predicted to adversely affect calcium binding or protein folding. Functional studies of the variants were not performed. Compared to pituitary adenomas with wildtype CDH23, those associated with CDH23 mutations were smaller in diameter and less invasive. Heterozygous, putatively functional variants in the CDH23 gene were found in 2 (0.8%) of 260 control individuals.

▼ Genotype/Phenotype Correlations
DFNB12 is associated with CDH23 missense mutations that are presumed to be hypomorphic alleles with sufficient residual activity for retinal and vestibular function, but not for auditory cochlear function. In contrast, homozygous nonsense, frameshift, splice site, and some missense mutations of CDH23, or a combination of these USH1D alleles in a compound heterozygote, cause USH1D. Schultz et al. (2011) identified 12 different homozygous CDH23 mutations, including 8 novel mutations, in 13 families with DFNB12. All were missense, except 1 in-frame deletion. Ten different homozygous mutations were found in 14 families and 1 singleton with USH1D. These latter mutations were mostly nonsense, frameshift, or splice site mutations, but there was 1 in-frame deletion and 2 missense mutations. Affected individuals in 3 additional families were found to carry compound heterozygous mutations in the CDH23 gene, with the different alleles being associated with either DFNB12 or USH1D. Based on the phenotypes within families, the results indicated that USH1D occurs only when there are 2 USH1D alleles in trans. In contrast, when there is a DFNB12 allele in trans with a USH1D allele, the phenotype is DFNB12. The findings indicated that a DFNB12 allele is phenotypically dominant to a USH1D allele, and can preserve normal retinal and vestibular function even in the presence of a USH1D allele. Schultz et al. (2011) noted the implications for genetic counseling.

▼ Animal Model
Di Palma et al. (2001) identified loss-of-function mutations in the Cdh23 gene in each of 3 different waltzer alleles. They demonstrated that Cdh23 is expressed in the neurosensory epithelium. During early hair cell differentiation, stereocilia organization was disrupted in homozygotes for one of the mutant alleles. The data indicated that Cdh23 is a critical component of hair bundle formation. The demonstration of mutations in the human CDH23 gene in USH1D established waltzer as the mouse model for USH1D.

Age-related hearing loss (AHL) in common inbred mouse strains is a genetically complex quantitative trait. Noben-Trauth et al. (2003) found a synonymous single-nucleotide polymorphism (SNP) in exon 7 of the Cdh23 gene that showed significant association with AHL and the deafness modifier mdfw (modifier of deafwaddler). The hypomorphic Cdh23(753A) allele caused in-frame skipping of exon 7. Altered adhesion or reduced stability of CDH23 may confer susceptibility to AHL. Homozygosity at Cdh23(753A) or in combination with heterogeneous secondary factors was found to be a primary determinant of AHL in mice.

Zheng et al. (2005) generated mice that were heterozygous for both Cdh23(v-2J) and Pcdh15(av-3J) (605514) mutations on a uniform C57BL/6J background. Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls, which supported a digenic model of hearing loss. Cytoarchitectural defects in the cochlea of digenic heterozygotes, including degeneration of the stereocilia and a base-apex loss of hair cells and spiral ganglion cells, were consistent with the observed age-related hearing loss of these mice beginning with the high frequencies. The authors noted that while hearing loss was progressive in these animals, humans with heterozygosity for both CDH23 and PCDH15 mutations are congenitally deaf. Zheng et al. (2005) concluded that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.

In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, Schwander et al. (2009) identified 'salsa' mice, which suffer from progressive hearing loss and carry a Cdh23 mutation (E737V) that is predicted to affect Ca(2+) binding by the extracellular domain. Otoacoustic emissions were not detected, suggesting a defect in outer hair cell function. Similar mutations in the human CDH23 gene cause DFNB12. Although hair bundle development appeared unaffected in salsa mice, tip links were progressively lost, resulting in hair cell death. Tip links in vestibular hair cells were unaffected. Biochemical studies showed that mutant Cdh23 had impaired interaction with Pcdh15. The findings suggested that missense mutations in DFNB12 patients lead to deafness by affecting tip links.

Bahloul et al. (2010) found that knockout of Cdh23 in mice resulted in loss of harmonin from the apex of hair bundles in the organ of Corti and caused redistribution of a weakened myosin-7a signal along stereocilia.

▼ ALLELIC VARIANTS ( 19 Selected Examples):

.0001 USHER SYNDROME, TYPE ID
CDH23, GLN1496HIS
In a Cuban family with Usher syndrome type ID (USH1D; 601067), Bolz et al. (2001) identified a G-to-C transversion at nucleotide 4488 of the CDH23 gene, leading to a gln1496-to-his (Q1496H) mutation. The mutation resulted in aberrant splicing in an in vitro assay. Homozygotes for this mutation had a severe course of retinal disease.

.0002 USHER SYNDROME, TYPE ID
CDH23, ARG1746GLN
In a Cuban family with Usher syndrome type ID (USH1D; 601067), Bolz et al. (2001) identified a G-to-A transition at nucleotide 5237 of the CDH23 gene, resulting in an arg1746-to-gln (R1746Q) mutation. Homozygotes for this mutation had mild retinitis pigmentosa.

.0003 USHER SYNDROME, TYPE ID
CDH23, 3-BP DEL, 3841ATG
In a German patient with Usher syndrome type ID (USH1D; 601067), Bolz et al. (2001) identified compound heterozygosity for 2 mutations in the CDH23 gene: a 3-bp deletion at nucleotide 3841, resulting in the deletion of met1281, and a G-to-A transition at the +5 position of intron 51 (605516.0004).

.0004 USHER SYNDROME, TYPE ID
CDH23, IVS51, G-A, +5
For discussion of the G-to-A transition at the +5 position of intron 51 in the CDH23 gene that was found in compound heterozygous state in a patient with Usher syndrome type ID (USH1D; 601067) by Bolz et al. (2001), see 605516.0003.

.0005 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, ASP1243ASN
In affected members of a family with autosomal recessive deafness-12 (DFNB12; 601386), Bork et al. (2001) identified an asp1243-to-asn (D1243N) mutation in the CDH23 gene.

.0006 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, ASP1400ASN
In a family with autosomal recessive deafness-12 (DFNB12; 601386), Bork et al. (2001) found that affected members had an asp1400-to-asn (D1400N) mutation in the CDH23 gene.

.0007 USHER SYNDROME, TYPE ID
CDH23, GLN492TER
In a family with Usher syndrome type ID (USHID; 601067), Bork et al. (2001) found that affected members had a gln492-to-ter (Q492X) mutation in the CDH23 gene.

.0008 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, ASP2148ASN
In 2 presumably unrelated families with autosomal recessive nonsyndromic deafness mapping to chromosome 10q (DFNB12; 601386), Astuto et al. (2002) found an asp2148-to-asn (D2148N) mutation in the CDH23 gene, located in exon 47 in extracellular domain 20.

De Brouwer et al. (2003) performed a genetic analysis of a large consanguineous family with DFNB12 that was previously described by Marres and Cremers (1989). Patients in 1 branch of the family were homozygous for the 35delG mutation in the GJB2 gene (121011.0005) causing DFNB1 (220290). Patients in 2 other branches carried 2 novel mutations in the CDH23 gene causing DFNB12: a homozygous 6442G-A transition in exon 47 causing the D2148N mutation in 1 branch, and compound heterozygosity for this mutation and a 4021G-A transition causing an asp1341-to-asn (D1341N) mutation (605516.0009).

.0009 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, ASP1341ASN
For discussion of the asp1341-to-asn (D1341N) mutation in the CDH23 gene that was found in compound heterozygous state in patients with autosomal recessive deafness-12 (DFNB12; 601386) by de Brouwer et al. (2003), see 605516.0008.

.0010 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, PHE1888SER
In 5 sibs, born of consanguineous parents, with autosomal recessive deafness-12 (DFNB12; 601386), Schultz et al. (2005) identified a homozygous 5663T-C transition in exon 42 of the CDH23 gene, resulting in a phe1888-to-ser (F1888S) substitution in the extracellular domain of the protein. Two of the sibs had high frequency hearing loss and 3 had severe to profound hearing loss affecting all frequencies. The 3 severely affected sibs were heterozygous for a val586-to-met substitution in the ATP2B2 gene (V586M; 108733.0001). Variants in ATP2B2, the plasma membrane calcium pump, modulate the severity of hearing loss in mice with mutations in the CDH23 gene (Noben-Trauth et al., 2003).

.0011 USHER SYNDROME, TYPE ID
USHER SYNDROME, TYPE ID/F, DIGENIC, INCLUDED
CDH23, 1-BP DEL, 193C
In a proband with a diagnosis of Usher syndrome type I (see 601067), Zheng et al. (2005) found compound heterozygosity for a 1-bp deletion of the CDH23 gene, 193delC, and a 3-bp deletion in the PCDH15 gene (605514.0005). The 193delC mutation was previously found in a patient with Usher syndrome type ID (USH1D) by Astuto et al. (2002). The CDH23 193delC mutation consists of deletion of a single C in a CCCCC string in exon 3, which causes a frameshift at codon 65 in the first extracellular repeat domain and a stop codon 48 amino acids downstream. The resulting truncated protein lacked approximately 96% of the predicted coding sequence.

.0012 USHER SYNDROME, TYPE ID/F, DIGENIC
CDH23, ARG3189TRP
In a proband with a diagnosis of Usher syndrome type I (see 601067), Zheng et al. (2005) found compound heterozygosity for a C-to-T transition at nucleotide 9565 of the CDH23 gene and a 1-bp deletion in the PCDH15 gene (16delT; 605514.0008). The 9565C-T mutation causes a substitution of trp for arg at codon 3189 in the cytoplasmic region of the CDH23 protein (R3189W) and was predicted to affect protein-protein interaction.

.0013 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
CDH23, THR1209ALA
This variant, formerly titled USHER SYNDROME, TYPE ID/USHER SYNDROME, TYPE ID/F, has been reclassified based on the findings of Bell et al. (2011).

In a proband with a diagnosis of Usher syndrome type I (see 601067), Zheng et al. (2005) found homozygosity for an A-to-G transition at nucleotide 3625 of the CDH23 gene resulting in a thr1209 to ala substitution (T1209A), and an additional 3-bp deletion in the PCDH15 gene (605514.0005). The authors noted that the CDH23 T1209A mutation had been found in homozygosity in a family with USH1D (Astuto et al., 2002). The T1209A substitution is located within a linker region between extracellular repeat domains 11 and 12. Zheng et al. (2005) noted that their patient had a particularly severe Usher syndrome type I phenotype.

In a preconception carrier screen for 448 severe recessive childhood diseases involving 437 target genes, Bell et al. (2011) found that the T1209A mutation in CDH23 is a polymorphism carried by unaffected individuals.

.0014 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, PRO240LEU
In affected individuals from 2 unrelated Japanese families with autosomal recessive deafness-12 (DFNB12; 601386), Wagatsuma et al. (2007) identified compound heterozygosity for a 719C-T transition in exon 7 of the CDH23 gene, resulting in a pro240-to-leu (P240L) substitution in extracellular domain 3, and a 902G-A transition in exon 9 of the CDH23 gene, resulting in an arg301-to-gln (R301Q; 605516.0015) substitution in extracellular domain 3.

.0015 DEAFNESS, AUTOSOMAL RECESSIVE 12
CDH23, ARG301GLN
For discussion of the arg301-to-gln (R301Q) mutation in the CDH23 gene that was found in compound heterozygous state in patients with autosomal recessive deafness-12 (DFNB12; 601386) by Wagatsuma et al. (2007), see 605516.0014.

.0016 PITUITARY ADENOMA 5, MULTIPLE TYPES
CDH23, ARG1379LEU
In 4 members of a family with pituitary adenomas (PITA5; 617540), Zhang et al. (2017) identified a heterozygous c.4136G-T transversion (c.4136G-T, NM_022124.5) in the CDH23 gene, resulting in an arg1379-to-leu (R1379L) substitution at a highly conserved residue in the second calcium-binding site of the EC13 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project or ExAC databases. Molecular modeling predicted that the mutation would impair calcium-binding ability and stability of the EC domain, suggesting that it is an inactivating mutation and would impair cell-cell adhesion. However, immunostaining showed that mutant CDH23 localized to the membrane of normal pituitary glands as well as pituitary adenomas, with similar expression levels as wildtype. Two patients had growth hormone-secreting adenomas and 2 had nonfunctional adenomas. Two unaffected family members also carried the mutation, but these individuals were younger than 30 years old and may still develop the disorder.

.0017 PITUITARY ADENOMA 5, GROWTH HORMONE-SECRETING
CDH23, ARG2115HIS
In 2 sisters with growth hormone-secreting pituitary adenomas (PITA5; 617540), Zhang et al. (2017) identified a heterozygous c.6344G-A transition (c.6344G-A, NM_022124.5) in the CDH23 gene, resulting in an arg2115-to-his (R2115H) substitution at a highly conserved residue in 1 of the EC domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project or ExAC databases. Two unaffected family members also carried the mutation, suggesting incomplete or age-dependent penetrance. Functional studies of the variant and studies of patient cells were not performed.

.0018 PITUITARY ADENOMA 5, NONFUNCTIONAL
CDH23, ARG3138TRP
In 3 members of a family with nonfunctional pituitary adenomas (PITA5; 617540), Zhang et al. (2017) identified a heterozygous c.9412C-T transition (c.9412C-T, NM_022124.5) in the CDH23 gene, resulting in an arg3138-to-trp (R3138W) substitution at a highly conserved residue in 1 of the EC domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project or ExAC databases. Two unaffected family members also carried the mutation, suggesting incomplete or age-dependent penetrance. Functional studies of the variant and studies of patient cells were not performed.

.0019 PITUITARY ADENOMA 5, NONFUNCTIONAL
CDH23, ASP3296ASN
In 3 members of a family with nonfunctional pituitary adenomas (PITA5; 617540), Zhang et al. (2017) identified a heterozygous c.9886G-A transition (c.9886G-A, NM_022124.5) in the CDH23 gene, resulting in an asp3296-to-asn (D3296N) substitution at a highly conserved residue in 1 of the EC domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, but was found at a very low frequency in the ExAC databases. One unaffected family member also carried the mutation, suggesting incomplete or age-dependent penetrance. Functional studies of the variant and studies of patient cells were not performed.

Tags: 10q22.1