DiagnosisClinical Diagnosis CATSPER-related male infertility results from abnormalities in sperm and can be either:Nonsyndromic (CATSPER-related nonsyndromic male infertility [NSMI])
orAssociated with non-progressive prelingual sensorineural hearing loss (deafness-infertility syndrome [DIS])The diagnosis of either NSMI or DIS can be made only by molecular genetic testing.TestingSperm analysis. Routine semen analysis assesses sperm number, morphology, and motility and the function of the genital tract (semen volume and pH) [WHO 1999] (Table 1). Note: Although routine semen analysis effectively identifies azoospermia, changes in sperm morphology and motility can be missed unless the analysis includes measurement of sperm motility (e.g., path velocity, progressive velocity, and track speed). NSMI. Clinical analysis of semen from affected males in both families showed sperm defects and reduced fertility. The analysis included measurement of volume, pH, sperm count, sperm motility, and sperm form (structure). While the pH of the semen was in the normal range, examination of all other parameters revealed non-motile sperm or sperm motility below the normal threshold, low sperm count, an increased number of abnormally structured spermatozoa, and reduced semen volume [Avenarius et al 2009].DIS. Semen analysis of males with DIS is normal for sperm count and semen volume, but sperm morphology and motility are abnormal. For example, in one patient more than 88% of sperm were malformed (mainly thin heads, micro- and irregular acrosomes) and approximately 30% of sperm had short, coiled flagella [Zhang et al 2007]. Following liquidation fewer than 5% of sperm had full swimming capacity. Similar defects were observed in affected males from the other three families [Avidan et al 2003, Zhang et al 2007].Table 1. Semen Analysis View in own windowTestCATSPER-Related Male InfertilityNormal ^{1NSMIDISEjaculate volume 0.4-1.0 mL1-4 mL1.5-5 mLpH7.5-8.0 Nl>7.2 Sperm concentration NI60-78 million/mL>20 million/mL Total sperm number (million/ejaculate)10.4-12 >40>40Percent motility (% motile)0%-50%1%-5%>50%Forward progression (scale 0-4)NINI>2Morphology (% normal)20%-65%9%-12%>30%Sperm agglutination (scale 0-3)NINI<2Viscosity (scale 0-4)NINormal - 3+<3NSMI=nonsyndromic male infertilityDIS=deafness-infertility syndrome1. Values from ASRM Practice Committee [Male Infertility Best Practice Policy Committee 2006] Hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction) should be completed. In DIS the hearing loss is prelingual in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz). Vestibular function is normal.Molecular Genetic TestingGenesCATSPER1 mutations are associated with NSMI (CATSPER-related nonsyndromic male infertility).A contiguous gene deletion at chromosome 15q15.3 including CATSPER2 and STRC is associated with DIS (deafness-infertility syndrome). Evidence for locus heterogeneity. The contribution of the other CATSPER gene family members (CATSPER2, CATSPER3, CATSPER4, CATSPERβ, and CATSPERG) to NSMI is unknown [Lobley et al 2003, Liu et al 2007, Cai & Clapham 2008, Wang et al 2009, Hildebrand et al 2010]. Table 2. Summary of Molecular Genetic Testing Used in CATSPER-Related Male InfertilityView in own windowGene SymbolProportion of CATSPER-Related NSMI and DIS Attributed to Mutations in This Gene 1Test MethodMutations DetectedTest AvailabilityCATSPER1Unknown for NSMISequence analysis (see Table 4)Clinical CATSPER2 and STRC 2100% for DISDeletion/ duplication analysis 3Contiguous gene deletion 2 (see Table 5)Research onlyNSMI = nonsyndromic male infertilityDIS = deafness-infertility syndrome1. The contribution of the other CATSPER gene family members (CATSPER2, CATSPER3, CATSPER4, CATSPERB, and CATSPERG) to NSMI is unknown. 2. In all cases of DIS caused by mutation in CATSPER2, the entire CATSPER2 gene has been deleted as part of a contiguous gene deletion that also includes STRC (see Molecular Genetics).3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To establish the diagnosis in a proband1.Clinical evaluation (physical examination, semen analysis, audiology)2.Molecular genetic testingSequence analysis of CATSPER1 for males with NSMIDeletion/duplication analysis for males with DIS Carrier testing for at-risk relatives requires prior identification of the causative mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the causative mutations in the family.Genetically Related (Allelic) Disorders CATSPER1. No phenotypes other than those discussed in this GeneReview are known to be caused by mutations in CATSPER1.CATSPER2. No phenotypes other than those discussed in this GeneReview are known to be caused by deletion or mutation of CATSPER2; however, mutations in STRC (part of the CATSPER2 contiguous gene deletion and responsible for the deafness associated with the DIS phenotype) cause autosomal recessive nonsyndromic hearing loss at the DFNB16 locus [Verpy et al 2001]. Deletion or mutation of CATSPER2 has not been associated with nonsyndromic hearing loss.}

Natural History CATSPER-related male infertility includes CATSPER-related nonsyndromic male infertility (NSMI) and the deafness-infertility syndrome (DIS) [Nikpoor et al 2004, Clapham & Garbers 2005, Benoff et al 2007, Hildebrand et al 2010].CATSPER-related nonsyndromic male infertility. NSMI caused by mutations in CATSPER1 was first reported in two unrelated Iranian families in 2009 [Avenarius et al 2009]. In both families, the affected infertile males were offspring of first-cousin marriages. Females homozygous for the CATSPER1 mutation and all heterozygous individuals within a family have normal fertility.Deafness-infertility syndrome (DIS). DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and congenital dyserythropoietic anemia type 1 (caused by mutation of CDAN1). The three affected males were homozygous for a p.Asn598Ser missense mutation in CDAN1 and were also homozygous for a contiguous gene deletion that involved CATSPER2 and STRC [Avidan et al 2003]. Four years later, three unrelated Iranian families that segregated only deafness and infertility secondary to deletion of CATSPER2 and STRC were identified [Zhang et al 2007]. Zhang and colleagues designated this new syndromic form of hearing loss as deafness-infertility syndrome (DIS). None of these families share similar deletions.All males homozygous for CATSPER2-STRC deletion are infertile. The penetrance for the hearing loss in affected males and females who are homozygous for the deletion of CATSPER2-STRC in DIS is 100% although onset and severity of hearing loss may vary. Knijnenburg and colleagues reported a male of non-consanguineous parentage with a complex phenotype that included intellectual disability, short stature, dysmorphic features, and hearing loss associated with a homozygous CATSPER2-STRC contiguous gene deletion. Because the proband was only ten years old, sperm motility could not be assessed. The more severe phenotype in this individual may represent one end of a broader phenotypic spectrum associated with homozygous deletion of 15q15.3 or the intellectual disability and dysmorphic features may be unrelated or only partially related to the 15q15.3 deletion [Knijnenburg et al 2009]. Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal. In all reported affected males, the degree of hearing loss is moderate-to-severe across all frequencies (0.25 kHz-8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [Verpy et al 2001, Villamar et al 1999].

Differential DiagnosisTable 3. Spermatogenic Failure: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM numberGene/LocusGene/Locus
MIM number?Globozoospermia 102530 GOPC, PIST, FIG, CAL 606845 Spermatogenic failure 1 258150 SPGF1 258150 Spermatogenic failure 2 108420 SPGF2, ASG 108420 Spermatogenic failure 3 606766 SPGF3, AZON 606766 Spermatogenic failure 4 270960 SYCP3, SCP3, COR1, SPGF4 604759 Spermatogenic failure 5 243060 STK13, AIE2, SPGF5 603495 Spermatogenic failure 6 102530 SPATA16, SPGF6 609856 Spermatogenic failure 7 612997 CATSPER1, CATSPER, SPGF7 606389 Spermatogenic failure 8 613957 NR5A1, FTZF1, FTZ1, SF1, AD4BP, POF7, SRXY3, SPGF8 184757 Spermatogenic failure 9 613958 DPY19L2, SPGF9 613893 Spermatogenic failure, X-linked, 2 309120 SPGFX2 309120 Spermatogenic failure, Y-linked, 1 400042 DELYq11, CYDELq11, SPGFY1 400042 Spermatogenic failure, Y-linked, 2 415000 USP9Y, DFFRY, SPGFY2 400005 Data from Online Mendelian Inheritance in ManMale infertility. In approximately half of the 15% of couples who cannot conceive, the cause is ascribed to male infertility as described by Mosher & Pratt [1990] and Templeton et al [1990]. Causes of male infertility other than CATSPER mutation are numerous and include but are not limited to:Obstruction of the ejaculatory ducts (e.g., cystic fibrosis [CF] and congenital bilateral absence of the vas deferens [CBAVD]) (see CFTR-Related Disorders)Abnormal sperm motility (see Primary Ciliary Dyskinesia) Immunologic abnormalities (e.g., anti-sperm antibodies)Infection (e.g., mumps orchitis, epididymitis, urethritis)Vascular abnormalities (e.g., varicocele)TraumaEndocrine abnormalities (e.g., congenital adrenal hyperplasia [see 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia], isolated follicle-stimulating hormone [FSH] deficiency, hyperprolactinemia [see Hypogonadotropic Hypogonadism Overview])Testicular tumorExposure to toxic agents (e.g., radiation, chemotherapy agents, heat)Klinefelter syndrome (XXY)Balanced chromosome rearrangementsSertoli-cell-only syndrome (SCOS)For review of these differential diagnoses refer to Y Chromosome Infertility [Disteche 2012].Molecular genetic testing to attempt to identify the involved gene is appropriate. Mutations in a large number of genes cause male infertility (a partial list includes CATSPER1, AKAP3, AKAP4, DNAH1, DNAH5, DNAH11, SPATA16, PRM1, PRM2, SYCP1, and SYCP3); as asthenospermia (loss or reduction in spermatozoa motility) is caused by mutations in CATSPER1 (NSMI) [Avenarius et al 2009] and CATSPER2 (DIS) [Avidan et al 2003, Zhang et al 2007], the CATSPER family should be among the first genes tested. Deafness. See Deafness and Hereditary Hearing Loss Overview.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).CATSPER-related nonsyndromic male infertility CATSPER-related DIS, males CATSPER-related DIS, females

ManagementEvaluations Following Initial Diagnosis The extent of disease in a male diagnosed with CATSPER-related infertility can be determined by:Semen analysis to assess sperm number, motility, and morphologyAudiologic evaluationMedical genetics consultationTreatment of ManifestationsInfertility. No available treatment can reverse the morphologic and/or motility defects observed in CATSPER-related asthenospermia or asthenoteratospermia (low motility with increased number of abnormal forms). For infertile males, an option to conception is to bypass these morphologic and motility abnormalities using assisted reproductive technologies (ARTs) like intracytoplasmic sperm injection (ICSI). This approach has been successfully used in males with DIS [Zhang et al 2007]. Its use in males with CATSPER1-related NSMI has not been reported.Deafness. For males with DIS, treatment of hearing loss is best achieved by fitting hearing aids for amplification. For school-age children or adolescents, special educational assistance may also be warranted and, where possible, should be offered. (See Related Genetic Counseling Issues for other issues pertinent to the care of deaf and hard-of-hearing persons.)SurveillanceAnnual monitoring of hearing loss is not required in individuals with DIS because hearing loss is non-progressive.Agents/Circumstances to AvoidIndividuals with DIS should avoid exposure to loud noise in the workplace or during recreation.Evaluation of Relatives at RiskIn DIS, molecular genetic testing in infancy or early childhood can determine whether an at-risk child has inherited the causative contiguous gene deletion; early support and management can then be provided. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. CATSPER-Related Male Infertility: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCATSPER111q13​.1Cation channel sperm-associated protein 1CATSPER1 homepage - Mendelian genesCATSPER1CATSPER215q15​.3Cation channel sperm-associated protein 2CATSPER2 homepage - Mendelian genesCATSPER2STRC15q15Stereocilin Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for CATSPER-Related Male Infertility (View All in OMIM) View in own window 606389CATION CHANNEL, SPERM-ASSOCIATED, 1; CATSPER1 606440STEREOCILIN; STRC 607249CATION CHANNEL, SPERM-ASSOCIATED, 2; CATSPER2 611102DEAFNESS, SENSORINEURAL, AND MALE INFERTILITY 612997SPERMATOGENIC FAILURE 7; SPGF7Molecular Genetic Pathogenesis NSMI. Despite the fact that a significant number of genes are implicated in NSMI [Matzuk & Lamb 2008], the genetic etiology often goes undiagnosed in the absence of more rigorous characterization of the sperm phenotype that includes measurement of sperm motility parameters like path velocity, progressive velocity, and track speed. These parameters are all markedly impaired in CatSper1-/- (knockout) mouse sperm as compared to wild-type sperm [Ren et al 2001].DIS. Deletion of CATSPER2 is the cause of infertility in males with DIS based on murine data showing that independent loss of CATSPER2 protein in sperm leads to infertility in males [Ren et al 2001, Qi et al 2007, Avenarius et al 2009]. Deletion of STRC, which encodes stereocilin, underlies the hearing loss in DIS. Mutations of only STRC result in autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB16 locus [Verpy et al 2001]. This is supported by the generation of Strc-/- (knockout) mice that have a specific outer hair cell defect, while their inner hair cells appear unaffected [Verpy et al 2001]. Inactivation of Strc in mouse leads to failure of the cochlear amplifier [Verpy et al 2008]. This murine phenotype is in agreement with the moderate-to-severe hearing loss usually observed in individuals with DFNB16 or DIS. CATSPER1Normal allelic variants. CATSPER1 has a transcript length of 2,634 base pairs with 12 exons (NM_053054.3). Pathologic allelic variants. The two known pathologic allelic variants are located in exon 1 of CATSPER1. This exon encodes a domain of unknown function. Both alleles are insertion mutations leading to a frameshift and a premature stop codon. See Table 3. Based on this data nonsense mutations of CATSPER1 are predicted to result in NSMI, although none have been reported to date [Avenarius et al 2009]. The mutations in Table 3 are the only two reported for CATSPER1 to date [reviewed in Hildebrand et al 2010]. It is not known whether less disruptive gene alterations (e.g., missense mutations) also lead to NSMI.Table 4. Selected CATSPER1 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)Reference SequencesEthnicity of FamilyPhenotypec.539dupT ^{2p.His182Profs*8
(Lys180Lysfs*8)NM_053054​.3 NP_444282​.3IranianNSMIc.944_948dup
(948-949insATGGC) 2p.Asp317Metfs*20IranianNSMISee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Avenarius et al [2009]Normal gene product. CATSPER1 protein is a 780-amino acid calcium channel that most closely resembles a single six-transmembrane-spanning repeat of the voltage-dependent calcium channel four-repeat structure. CATSPER is vital to cAMP-mediated calcium influx, sperm motility and fertilization [Ren et al 2001].Abnormal gene product. Reported mutations in CATSPER1 are insertion mutations in exon 1 that lead to frameshift and premature stop codons. These changes are predicted to lead to complete loss of CATSPER1 protein as a result of nonsense-mediated decay (NMD) or truncated proteins lacking all transmembrane domains and the channel pore.CATSPER2Normal allelic variants. CATSPER2 comprises 13 exons and has a transcript length of 1948 base pairs (NM_172095.1). Pathologic allelic variants. See Table 5. In all cases of DIS resulting from homozygous CATSPER2-STRC deletion, the entire CATSPER2 gene is deleted [Avidan et al 2003, Zhang et al 2007, reviewed in Hildebrand et al 2010]. It is unclear whether nonsense or missense mutations in CATSPER2 would lead to a NSMI phenotype.Table 5. Selected CATSPER2/STRC Pathologic Allelic VariantsView in own windowChromosome RearrangementGenes Deleted Reference SequencesEthnicity of FamilyPhenotypeDel(15)(q15.1-q15.3) 1CATSPER2} and STRCCATSPER2 isoform 1:
NM_172095​.1 NP_742093​.1
STRC:
NM_153700​.2
NP_714544​.1French (n=1)
Iranian (n=3)DISSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Avidan et al [2003], Zhang et al [2007]Normal gene product. CATSPER2 protein is 530 amino acids in length. It is one of several sperm-specific voltage-gated ion channels that hav a Ca²⁺ ion-selective pore domain that is required for sperm cell motility [Quill et al 2001, Qi et al 2007].Abnormal gene product. Reported mutations in CATSPER2 are deletion of the entire gene as part of a contiguous gene deletion syndrome [Avidan et al 2003]. The deletion is predicted to result in complete absence of CATSPER2 protein.STRCNormal allelic variants. STRC is a 29-exon gene and has a transcript length of 5,515 base pairs (NM_153700.2).Pathologic allelic variants. The only known pathologic allelic variants of STRC in individuals with DIS are contiguous deletions that also delete CATSPER2 [Avidan et al 2003, Zhang et al 2007] (see Table 5). Normal gene product. STRC protein is 1775 amino acids in length (NP_714544.1). It is expressed in the stereocilia hair-bundle of outer hair cells, the inner ear cells that amplify the initial stimulation [Verpy et al 2008]. A deletion of the contiguous genes CATSPER2 and STRC result in the DIS phenotype; intragenic mutation in STRC results in autosomal recessive nonsyndromic hearing loss at the DFNB16 locus [Verpy et al 2001, Avidan et al 2003, Zhang et al 2007, Knijnenburg et al 2009].Abnormal gene product. Reported mutations in STRC that cause DIS are homozygous deletions of the entire gene as part of contiguous gene deletion that includes CATSPER2; deletion of STRC results in loss of its encoded protein, stereocilin.