Catsper-Related Male Infertility

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2021-01-18

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Summary

Clinical characteristics.

CATSPER-related male infertility results from abnormalities in sperm and can be either CATSPER-related nonsyndromic male infertility (NSMI) or the deafness-infertility syndrome (DIS) when associated with non-progressive prelingual sensorineural hearing loss. Males with NSMI have infertility while females have no symptoms. Males with DIS have both infertility and hearing loss, while females have only hearing loss. Routine semen analysis typically identifies abnormalities in sperm number, morphology, and motility. Otologic examination and audiologic assessment can identify hearing loss.

Diagnosis/testing.

The diagnosis of CATSPER-related NSMI is established in males by the identification of biallelic pathogenic variants in CATSPER1. The diagnosis of DIS is established in both males and females by the identification of biallelic contiguous-gene deletions at chromosome 15q15.3 that includes both CATSPER2 and STRC.

Management.

Treatment of manifestations: For infertile males with DIS or CATSPER-related NSMI, assisted reproductive technologies such as intracytoplasmic sperm injection are likely to be an effective fertility option. For males with DIS, treatment of hearing loss is best achieved by fitting hearing aids for amplification and special educational assistance for school-age children.

Agents/circumstances to avoid: For individuals with DIS, exposure to loud noise.

Evaluation of relatives at risk: For sibs at risk for DIS, audiologic testing in infancy or early childhood to enable early management of hearing loss.

Genetic counseling.

CATSPER-related NSMI and DIS are inherited in an autosomal recessive manner. When both parents are carriers for pathogenic variants, each child has a 25% chance of inheriting both pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither pathogenic variant. Males who inherit two CATSPER1 pathogenic variants will be infertile; females who inherit two CATSPER1 pathogenic variants will have no signs/symptoms. Males who inherit two CATSPER2-STRC deletions will be infertile and deaf; females who inherit two CATSPER2-STRC deletions will be deaf. If the pathogenic variants have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Diagnosis

CATSPER-related male infertility results from abnormalities in sperm and can be either:

Nonsyndromic (CATSPER-related nonsyndromic male infertility [NSMI]); or
Associated with non-progressive prelingual sensorineural hearing loss (deafness-infertility syndrome [DIS]).

Suggestive Findings

CATSPER-related male infertility should be suspected in individuals with the following clinical features and semen analysis.

Clinical features

Male factor infertility
Hearing loss in either a male or female:
- In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
- Normal vestibular function

Semen 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. 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.

Table 1.

Semen Analysis

Test	CATSPER-Related Male Infertility		Normal ¹
Test	NSMI	DIS	Normal ¹
Ejaculate volume	0.4-1.0 mL	1-4 mL	1.5-5 mL
pH	7.5-8.0	Normal	>7.2
Sperm concentration	Normal	60-78 million/mL	>20 million/mL
Total sperm number (million/ejaculate)	10.4-12	>40	>40
Percent motility (% motile)	0%-50%	1%-5%	>50%
Forward progression (scale 0-4)	Normal	Normal	>2
Morphology (% normal)	20%-65%	9%-12%	>30%
Sperm agglutination (scale 0-3)	Normal	Normal	<2
Viscosity (scale 0-4)	Normal	Normal – 3+	<3

: DIS = deafness-infertility syndrome; NSMI = nonsyndromic male infertility
1.: Values from ASRM Practice Committee [Male Infertility Best Practice Policy Committee 2006]

Establishing the Diagnosis

Nonsyndromic Male Infertility (NSMI)

The diagnosis of CATSPER-related NSMI is established in males by the identification of biallelic loss-of-function pathogenic variants in CATSPER1 on molecular genetic testing (see Table 2).

Single-gene testing. Sequence analysis of CATSPER1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Alternate testing strategy for NSMI

A multigene panel that includes CATSPER1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Deafness-Infertility Syndrome (DIS)

The diagnosis of CATSPER-related DIS is established in both males and females by the identification of biallelic contiguous-gene deletions at chromosome 15q15.3 that includes both CATSPER2 and STRC.

Chromosomal microarray (CMA) using oligonucleotide or SNP arrays can detect a contiguous-gene deletion involving CATSPER2 and STRC in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q15.3 region.

Table 2.

Molecular Genetic Testing Used in CATSPER-Related Male Infertility

Gene ¹ or Deletion ²	Method	Proportion of Probands with Pathogenic Variants ³ Detectable by Method
Gene ¹ or Deletion ²	Method	NSMI	DIS
CATSPER1	Sequence analysis ⁴	2/2 ⁵	NA
CATSPER1	Gene-targeted deletion/duplication analysis ⁶	Unknown ⁷	NA
Homozygous deletion at 15q15.3 including CATSPER2 and STRC	CMA/array CGH ⁸	NA	100% ⁹
Unknown	NA	Unknown ¹⁰	Unknown ¹⁰

: DIS = deafness-infertility syndrome; NA = not applicable; NSMI = nonsyndromic male infertility
1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for details of the deletion and genes of interest included in the region.
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Two families with homozygous loss-of-function variants in CATSPER1 have been reported [Avenarius et al 2009].
6.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7.: No data on detection rate of gene-targeted deletion/duplication analysis in individuals with NSMI are available.
8.: Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays or array comparative genomic hybridization (array CGH) using fluorescent probesThese approaches are in clinical use targeting the 15q15.3 region. Note: The 15q15.3 deletion may not have been detectable by older oligonucleotide or BAC platforms.
9.: In all cases of CATSPER2-related DIS the entire CATSPER1 gene, as well as STRC, has been deleted as part of a contiguous deletion (see Molecular Genetics). A case of brothers with a heterozygous CATSPER2 deletion and an apparent NSMI phenotype has been reported; however, given the lack of a second pathogenic variant and no evidence of hearing loss, the cause of NSMI in this family was not clear [Jaiswal et al 2014].
10.: The contribution of the other CATSPER gene family members (CATSPER2, CATSPER3, CATSPER4, CATSPERB, 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].

Clinical Characteristics

Clinical Description

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)

CATSPER-related NSMI was 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 pathogenic variant and all heterozygous individuals within a family have normal fertility.

Deafness-Infertility Syndrome (DIS)

Infertility. All males homozygous for CATSPER2-STRC deletion are infertile. Semen analysis is typically abnormal. For example, in one affected male 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 other affected males from the four families [Avidan et al 2003, Zhang et al 2007, Smith et al 2013].

Hearing loss. All affected males and females who are homozygous for the deletion of CATSPER2-STRC have hearing loss, although onset and severity of hearing loss may vary.

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 [Villamar et al 1999, Verpy et al 2001].

Note: Knijnenburg and colleagues reported a male of nonconsanguineous 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. Sperm motility could not be assessed in the proband, who was age ten years. 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].

Genotype-Phenotype Correlations

Since only two pathogenic loss-of-function variants for CATSPER-related NSMI in two unrelated families have been identified [Avenarius et al 2009], meaningful genotype-phenotype correlations are not possible.

Similarly, all families with DIS have homozygous deletions at 15q15.3 involving loss of CATSPER2 and STRC [Avidan et al 2003, Zhang et al 2007, Knijnenburg et al 2009, Smith et al 2013, Gu et al 2015].

Historical Perspective

DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and congenital dyserythropoietic anemia type 1 (caused by pathogenic variants in CDAN1). The three affected males were homozygous for a p.Asn598Ser missense variant 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 deafness-infertility syndrome (DIS). None of these families share similar deletions.

Nomenclature

Deafness-infertility syndrome is also known as sensorineural deafness and male infertility.

CATSPER-related nonsyndromic male infertility is also referred to as autosomal recessive nonsyndromic male infertility.

Prevalence

The prevalence of CATSPER-related nonsyndromic male infertility (NSMI) is unknown; only two families have been reported.

The prevalence of deletions at 15q15.3 involving CATSPER2 and STRC was examined in peripheral blood specimens from 5,152 individuals from the general population by array CGH [Hoppman et al 2013]. Of those, 57 individuals (2 of whom were sibs) were found to be heterozygous for similar deletions including CATSPER2 and STRC, indicating that 1.09% of people in this sample were carriers. If this figure is representative of the general population, this would indicate that approximately one in 40,000 individuals is born with a homozygous deletion of this region, resulting in deafness and, in males, infertility [Hoppman et al 2013].

Differential Diagnosis

Male 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 pathogenic variants in CATSPER are numerous and include but are not limited to the following:

Obstruction of the ejaculatory ducts (e.g., cystic fibrosis and congenital absence of the vas deferens) (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)
Trauma
Endocrine abnormalities including congenital adrenal hyperplasia (see 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia), isolated follicle-stimulating hormone deficiency (OMIM 229070), and hyperprolactinemia (OMIM 615555)
Testicular tumor
Exposure to toxic agents (e.g., radiation, chemotherapy agents, heat)
Klinefelter syndrome (47,XXY)
Balanced chromosome rearrangements
Sertoli-cell-only syndrome

For review of these differential diagnoses refer to Y Chromosome Infertility: Differential Diagnosis.

Molecular genetic testing to attempt to identify the involved gene is appropriate. Pathogenic variants 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 pathogenic variants 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.

See Spermatogenic failure: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Deafness. See Deafness and Hereditary Hearing Loss Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CATSPER-related male infertility, the following evaluations are recommended (if not performed previously as part of the diagnostic evaluation):

In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Infertility. 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, one option is to bypass these morphologic and motility abnormalities using assisted reproductive technologies such as intracytoplasmic sperm injection (ICSI) [Smith et al 2013]. This approach has been used successfully in males with DIS [Zhang et al 2007].

Deafness. For males and females 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 Deafness and Hereditary Hearing Loss Overview and Related Genetic Counseling Issues for other issues pertinent to the care of deaf and hard-of-hearing persons.)

Prevention of Secondary Complications

Regardless of its etiology, uncorrected hearing loss has consistent sequelae. Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production.

Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention, whether through amplification, otologic surgery, or cochlear implantation, is effective [Smith et al 2005] (see Deafness and Hereditary Hearing Loss Overview).

Although decreased cognitive skills and performance in mathematics and reading are associated with deafness, examination of persons with hereditary hearing loss has shown that these deficiencies are not intrinsically linked to the cause of the deafness.

Thus, early identification and timely intervention are essential for optimal cognitive development in children with prelingual deafness.

Surveillance

Annual monitoring of hearing loss is not required in individuals with DIS because hearing loss is non-progressive.

Agents/Circumstances to Avoid

Individuals with DIS should avoid exposure to loud noise in the workplace or during recreation.

Evaluation of Relatives at Risk

It is appropriate to evaluate the sibs of a proband with DIS in infancy or early childhood in order to identify as early as possible those who would benefit from early support and management of hearing loss. Evaluations can include:

Molecular genetic testing for the causative contiguous-gene deletion;
Otologic examination and audiologic assessment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.