Genetics Testing In Couples with Infertility

This article discusses genetic testing in infertile couples, including male and female infertility, chromosomal aberrations, gene mutations, and Y-chromosomal microdeletions. It also covers polycystic ovary syndrome (POC), repeated pregnancy loss (RPL), and premature ovarian failure (POF).

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Genetics Testing In Couples with Infertility
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Table of Contents
Table of figures..........................................................................................................................3
Table of abbreviation.................................................................................................................4
Abstract......................................................................................................................................5
1.0 Introduction..........................................................................................................................6
1.1 Definitions........................................................................................................................6
2.0 Literature review..................................................................................................................7
2.1 Overall Reflexions on Genetic Testing............................................................................7
2.2 Male Infertility..................................................................................................................8
2.3 Genetic Testing in Male Infertility...................................................................................8
2.3.1 Chromosomal Aberrations.........................................................................................8
2.3.2 Klinefelter syndrome (karyotype 47, XXY including mosaics)................................8
2.3.3 Y-chromosomal microdeletions.................................................................................9
2.4 Female Infertility............................................................................................................10
2.5 Genetic Testing in Female infertility..............................................................................11
2.5.1 Polycystic ovary syndrome (POC)..........................................................................11
2.5.2 Repeated pregnancy loss..........................................................................................11
2.5.3 Premature ovarian failure.........................................................................................12
Conclusion................................................................................................................................12
References................................................................................................................................14

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Table of figures
Figure 2.1: Present model of Y chromosome microdeletion pattern...................................................10

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Table of abbreviation
CFTR- Cystic fibrosis trans-membrane receptor gene
WHO – World Health Organization
ICSI -Intracytoplasmic sperm injection
TESE -Testicular sperm extraction
TESE- Ovarian hyperstimulation syndrome
FSH – Follicle Stimulating Hormone
RPL- Repeated pregnancy loss
POF- Premature ovarian failure
PCOS- Polycystic ovary syndrome
SNP -Nucleotide polymorphism
ART- Aided reproductive technology

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Abstract
The decision to use genetic testing of infertile couples relies on the clinical findings. Patients
with extreme oligozoospermia and azoospermia should undergo Y-chromosomal micro-
deletion analysis and karyotype assessment as well that aberrations on the structure of the
chromosomes, Y chromosome microdeletions, and Klinefelter syndrome are ruled out. CFTR
screening is preferred for infertile patients diagnosed with obstructive azoospermia.
Professional counseling should accompany each genetic testing in both genders (Hotaling and
Carrell, 2014). Karyotype analysis is to be applied in investigating primary amenorrhea based
on the clinical symptoms of the patient. Cases of POF should be addressed using FMR1 gene
analysis and karyotype analysis. Currently, it is impossible to restore infertility in patients
with POF, however, in some instances, early detection through genetic screening can result in
the recommendation for early conception or extraction and preservation of the oocyte. Both
couples with RPL are recommended to undergo karyotype analysis (Romero et al., 2015), but
there is no endorsement for a standard genetic test for those with PCOS as of now.

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1.0 Introduction
Infertility is an illness that affects the reproductive system and is characteristic of the inability
to attain a clinical pregnancy after 48 weeks or more of usual unprotected sex. In all cases of
infertility, 40-50% are represented by female infertility, whereas male infertility accounts for
30-40% and the rest of 30% is not known or is accounted for by both male and female
infertility (Dyer et al., 2016). The Federal Statistical Office indicates that the cause of
unintentional childlessness in infertile couples looking for aided reproductive technology can
be ascribed to 11% male infertility to 24% female infertility, and 40% to both couples.
Nevertheless, the cause for infertility in 25% cases is unexplainable. Studies have indicated
that there is a high probability of the existence of genetic abnormalities such as gene
mutations and chromosomal anomalies in infertile couples. Advances in genetic studies have
led to the introduction of vitro fertilizing methods, and as a result, there exist genetic tests to
ascertain the reasons for infertility and examine the risks of a partner to transmit its genetic
features. This enables partners who are at-risk to make a well-versed decision when opting
for a clinically aided reproduction. Additionally, it allows the practitioners to carry out a
prenatal assessment if need be. The objective of this review is to present detailed information
on genetic testing of infertile couples. The study is divided into three parts: Overall
Reflexions on Genetic Testing, Genetic Testing in Male Infertility, and Genetic Testing in
Female Infertility.
1.1 Definitions
This unprotected sexual contact. The period of 12 months is provided for by the WHO (n.d.).
Infertility exists when pregnancy can only be attained via aided reproduction or if the partner
is wholly impotent.

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2.0 Literature review
2.1 Overall Reflexions on Genetic Testing
Genetic testing is usually carried out using three methods based on the current difficulty:
molecular cytogenetics, chromosome analysis, or molecular analysis of DNA. The
chromosomal analysis gives a summary of all chromosomes, which is adequate for
ascertaining aneuploidy. Fiorentino et al. (2014) define aneuploidy as the arithmetical
change from the normal number of 46 chromosomes like the case of Turner syndrome.
Aneuploidy also enables the recognition of changes in structures such as translocations
responsible for abortions. Fiorentino et al. (2014) further observe that the discovery of the
changes in the structures is significantly dependent on the microscopic resolution. The
German Society of Human Genetics recommends a minimum of 550 bands per haploid set of
chromosomal banding resolution in a situation where partners have experienced repeated
abortions. Greater microscopic resolutions within the microscopic range allow molecular
cytogenetic testing. Contrariwise, this approach is rarely used in fertility tests. Furthermore,
gene mutations require high-resolution tests for instance deletions in the azoospermia factor
area or FMR 1 gene mutations (Fiorentino et al., 2014).
Multiple scientific research has reliably indicated the prevalence of chromosomal aberrations
is the cause of infertile in couples irrespective of the cause of infertility. It is therefore also
recommended by multiple genetic testing guidelines and research that genetic testing should
commence with chromosome assessment at all times (Zorrilla and Yatsenko, 2013). A
minimum blood sample of 2ml diluted with heparin is recommended. However, a minimum
of 5 ml blood sample augmented with EDTA is needed in the case of molecular genetic
analysis (Fiorentino et al., 2014).

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2.2 Male Infertility
The leading cause of infertility in males are chromosomal aberrations, gene mutations (cystic
fibrosis trans-membrane receptor gene (CFTR)), and micro-deletions of Y chromosomes
(Hotaling and Carrell, 2014). Research on families of infertile couples shows that there is a
likelihood of a familial aspect in male infertility leading to a suggestion of an inherited
autosomal-recessive mechanism (Soubry et al., 2014). Hotaling and Carrell (2014) observe
that in male infertility, azoospermia and advanced oligozoospermia are the primary pointers
for genetic testing after semen assessment. Genetic testing should be carried out even if the
discovery of genetic alteration is less likely to alter the diagnosis. This is to ensure that a
causal diagnosis is finalized and the hereditary threat factor for the progenies is assessed in
case of favorable intervention (Hotaling and Carrell, 2014).
2.3 Genetic Testing in Male Infertility
2.3.1 Chromosomal Aberrations
Karyotype analysis is used to detect numerical and structural chromosomal abnormalities.
Chromosomal anomalies in infertile men are estimated to be approximately ten times higher
than the overall population, with a variation of 2% to 16% and declining sperm count and
increasing rate of aberrations of autosomes (Zhang et al., 2015). The infertile individual is in
most instances healthy except for syndromic cases. Contrariwise, translocation cases such as
a distinctly high risk of inducing pregnancy which will end up being a stillbirth or
miscarriage or an offspring with different levels of psychological or/and physical disability
due to an uneven set of chromosomes in the child (Hotaling and Carrell, 2014). Thus,
karyotype assessment is necessary for males diagnosed with azoospermia or oligospermia,
which should be followed by genetic psychotherapy.
2.3.2 Klinefelter syndrome (karyotype 47, XXY including mosaics)
The number of males with Klinefelter syndrome are markedly higher among infertile men
and have the following clinical symptoms azoospermia (fewer sperms in the ejaculate),

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reduced volume of the testis, high levels of gonadotropin, reduced concentrations of the
serum testosterone, and body structure that appears feminine. Azoospermia is the prevalent
cause of infertility in Klinefelter patients. The discovery of vitro fertilization alongside
intracytoplasmic sperm injection (ICSI) has increased the opportunity for Klinefelter men to
have their children. The latest research has shown that spermatozoa outcomes for ICSI are
30-70% successful when the testicular sperm extraction (TESE) is utilized (Madureira et al.,
2014). However, during the initial identification of Klinefelter syndrome, it is essential that
the practitioner to discuss with the client for the possibility of TESE even if conception is not
presently needed (Hotaling and Carrell, 2014).
2.3.3 Y-chromosomal microdeletions
Couples diagnosed with advanced oligozoospermia or mild azoospermia is supposed be
examined for the existence of microdeletions of the Y chromosomes, which are some of the
least detected genetic causes of spermatogenetic aberrations causing infertility in males
(Giacco et al., 2014). Hamada et al. (2013) identified five primary microdeletion forms
namely AZFa, AZFc, AZFb, P5-distal P1 AZFbc, and P4-distal P1 AZFc as shown in Figure
2.1. It is ascertained that microdeletions of the Y chromosome take place in men that are
infertile except for control men, however at a varying rate between states, based on the
criteria of selection of the participants and their ethnicity (Giacco et al., 2014). Overall, men
with azoospermia experience increased rates of microdeletions than those diagnosed with
oligozoospermia (Hotaling and Carrell, 2014). This is indicated by the semen features which
point out that 50% of the patients have azoospermia and few spermatozoa present in the
remaining 50% ejaculate (Hotaling and Carrell, 2014). Recurrent semen assessment is vital
for such patients because of the possibility of re-occurrence of the spermatozoa in the
ejaculate and is utilized for ICSI.

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Men with AZFc deletions can re-gain sperms by 50% using TESE. However, none has been
retrieved in cases of AZFb and AZFa deletions. Thus, molecular genetic testing is left as the
most appropriate for such patients with prognostic value for TESE. Inactivation of the
mutations may lead to primary or secondary amenorrhea, POF, and infertility, whereas
activation of mutations is likely to expose to ovarian hyperstimulation syndrome (OHSS)
caused by the administration of exogenous FSH or even with instant inception (Desai et al.,
2013).
Figure 2.1: Present classical Y chromosome microdeletion array
Figure 1 Figure 2.1: Present classical Y chromosome microdeletion array
Source: (Krausz et al., 2014).
2.4 Female Infertility
Female infertility is primarily caused by repeated pregnancy loss (RPL), premature ovarian
failure (POF), and polycystic ovary syndrome (PCOS).

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2.5 Genetic Testing in Female infertility
2.5.1 Polycystic ovary syndrome (POC)
High PCOS vulnerability is linked to multiple genes that regulate the function and
metabolism of the ovary. However, none is sufficiently powerful to individually correlate
with the vulnerability of the illness or response to therapy. Several research have examined
polymorphisms in the gene encrypting FSH receptor. In the study by Dewailly et al. (2013) a
single nucleotide polymorphism (SNP) in the tenth exon of the FSHR gene was unfailingly
detected being with a substantial relationship with ovarian feedback to FSH. However, it did
not appear to have any vital function in the PCOS. According to Yan et al. (2013), the FSH
quantity required for regulated ovarian hyperstimulation to attain the same level of estradiol
was markedly lower in females having the N/N genotype at point 680, pointing out to
decreased sensitivity of the ovary to FSH in vivo for an allele of the similar position.
2.5.2 Repeated pregnancy loss
Repeated pregnancy loss is justified when it repeatedly takes place thrice or more in
unprompted abortions before 20weeks of gestation. RPL takes place in 1% of all pregnancies.
Studies have suggested that specific immunological and thrombophilic abnormalities are the
possible causes of RPL (Keltz et al., 2013). Additionally, the authors have estimated that a
quarter to half of the miscarriages in patients with RPL are related to conceptus chromosomal
abnormality, and karyotyping of abortuses need to be undertaken to ascertain a cytogenetic
basis for the loss (Larsen et al., 2013). Pasquier et al. (2015) conducted abnormal tests on
women with over two RPL and indicated that there is a need for an entire assessment of the
evidence-based factors such as uterine anatomy, parental karyotyping among others.
Furthermore, the author suggests the recommendation of TSH to all partners with over two
successive losses of pregnancy. However, there is a need for restraint during the analysis of
the outcomes of an abnormal assessment because the factor ascertained may not be the cause
for the loss of pregnancy.

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2.5.3 Premature ovarian failure
POF is described as a deficiency of the primary ovary characterized by principal amenorrhea
or early exhaustion of the ovarian follicles before forty years (Chapman et al., 2015). There
is extreme heterogeneity about the causes of POF. It is necessary to carry out Karyotype
assessments in primary amenorrhea and when the disease is diagnosed at a tender age.
Studies have found that gene mutations influence the functions of hormone and follicle in
humans, but they are not mutual (Sherman et al., 2014). Oogenesis process involves genes i.e.
RNA linking proteins, transcription features, and DNA linking proteins. Credible mutations
that cause POF have been found in few women, however, in erratic instances. Therefore,
significant heterogeneity is present in POF, and no specific genetic testing approach can be
most appropriate except for karyotype. Sherman et al. (2014) elucidate that pre-mutations or
mutations of gene FMR1 are considerably linked with secondary amenorrhea in women
kinsfolks of males diagnosed with psychological problems.
A chance to foretell the possibility of premature menopause can be determined to sue early
diagnosis of POF in the family, an aspect that will also enable the assessment of varying
choices of reproduction such as giving birth earlier or freezing embryos. Jankowska (2017)
suggests that practitioners should carry out diagnosis on time and initiate managing the
symptoms, risk minimization, and emotional support, due to the severe aggregate negative
impacts of POF (Sherman et al., 2014). It is recommended that genetic counseling is
undertaken for multiple reasons, once any genetic type of POF is detected. According to
Sherman et al. (2014) counseling is beneficial in instances where families are associated with
mental retardation.
Conclusion
Most couples affected by infertility and the associated illnesses have resorted to aided
reproductive technology (ART). Studies have indicated that increasing age in women nears to

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menopause. Additionally, the practice of delaying childbirth favors the use of ART.
However, the efficacy of CSI treatment has led to concerns such as pregnancy complications
and congenital disabilities. This necessitates the need for genetic testing which enables early
detection of risks and mitigations through expert guidance and counseling.

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