Decoding Male Genetics: 5 Hidden Genetic Abnormalities Behind Male Infertility

If you and your partner have been trying to conceive without success, you are not alone. In couples experiencing infertility, male factors contribute to approximately 50% of all cases, and in roughly 15% of men with infertility, a specific genetic cause can be identified.

What often surprises our patients is this: a man can appear perfectly healthy, have normal sexual function, and show no symptoms at all — and still carry silent genetic abnormalities that only reveal themselves when a couple begins trying for a child.

Genetic screening before starting fertility treatment is not simply about finding a diagnosis. It is a practical step that directly shapes three important outcomes:

• Choosing the right treatment — for example, whether a surgical sperm retrieval (micro-TESE) is realistic, whether hormone therapy could restore fertility, or whether advanced embryo screening (PGT-SR) is appropriate
• Setting realistic expectations before you invest time, travel, and resources into assisted reproductive technology (ART)
• Protecting the health of your future children by understanding what can and cannot be passed down

This article explains the 5 most important genetic conditions affecting male fertility, with up-to-date clinical information drawn from international guidelines — the European Academy of Andrology (EAA/EMQN 2023), the European Consensus on Congenital Hypogonadotropic Hypogonadism, and the ASRM/AUA Male Infertility Guidelines (2024).

At SAFE Fertility Clinic in Bangkok, we apply these same international standards to every patient we care for — whether you live in Thailand or have traveled here from overseas.

1. Klinefelter Syndrome (47,XXY)

Klinefelter syndrome is the most common sex chromosome abnormality in men, affecting 1 in every 500 to 600 male births worldwide. It is also the single most common genetic cause of non-obstructive azoospermia (no sperm found in the semen despite the presence of the testes), accounting for roughly 11–14% of such cases.

Normally, a man has one X and one Y chromosome (46,XY). A man with Klinefelter syndrome has at least one extra X chromosome, giving him the pattern 47,XXY (classical form) or, in some cases, a mixed pattern called 46,XY/47,XXY mosaic, which usually carries a better prognosis.

The extra X chromosome disrupts testicular function. This leads to reduced testosterone production, shrinkage of the seminiferous tubules where sperm is normally made, and impaired sperm production. As a result, around 90% of men with classical Klinefelter syndrome have azoospermia, making natural conception not possible.

What the latest evidence shows (meta-analysis data):

A chromosomal analysis called karyotyping is the key diagnostic test. Once the diagnosis is confirmed, your fertility team can plan a treatment pathway — typically surgical sperm retrieval (PESA or micro-TESE) followed by IVF/ICSI.

Clinical Pearl:

Sperm retrieval rates decline with age. For men diagnosed with Klinefelter syndrome, sperm/fertility preservation should be considered before age 30–35. Favorable predictors of successful retrieval include testicular volume over 2 mL, LH under 21 IU/L, and mosaic karyotype.

For international patients:

A diagnosis of Klinefelter syndrome made overseas can typically be confirmed and acted upon at SAFE Fertility Clinic within a single visit of 2–3 weeks, combining karyotyping, hormonal assessment, and surgical sperm retrieval planning.

2. Congenital Hypogonadotropic Hypogonadism (CHH) / Kallmann Syndrome

This genetic condition affects the hormonal signals that tell the testes to produce sperm. It occurs when the brain cannot properly release Gonadotropin-Releasing Hormone (GnRH), a master hormone that controls reproduction. CHH affects 1 to 10 men per 100,000 live births.

An important point many patients — and even some clinicians — miss: only about 50% of men with CHH have a reduced or absent sense of smell (this subset is called Kallmann syndrome). The other 50% have a perfectly normal sense of smell — a variant called normosmic CHH. So if you can smell normally, that alone does not rule out CHH.

Without sufficient GnRH signaling, the body cannot produce the reproductive hormones FSH and LH in adequate amounts. When these hormones remain low, both sperm production and testosterone levels decline, leading to infertility.

Treatment outcomes — this is the most treatable condition of the five:

Important point to emphasize: Testosterone replacement alone does NOT restore sperm production. Many men with CHH are initially placed on testosterone for general symptoms, only to find that their fertility does not improve. To restore sperm production, you need gonadotropin injections or pulsatile GnRH therapy — not testosterone.

After successful treatment, natural pregnancy occurs in approximately 40% of couples, with an additional 20–30% achieving pregnancy through IVF/ICSI. Interestingly, about 10% of men with CHH experience spontaneous reversal after stopping therapy, meaning their own hormonal system may partially restart.

Genetic testing can identify the specific gene involved — over 25 genes have been linked to CHH, including ANOS1, FGFR1, PROKR2, GNRHR, KISS1R, and TACR3. Knowing the gene helps guide counseling for your future children, as some mutations have different inheritance patterns.

✈ For international patients: CHH treatment typically requires 12–24 months of hormone therapy. Many of our international patients begin treatment in Bangkok and continue it at home, returning to SAFE Fertility Clinic for periodic monitoring and eventual semen analysis or ART cycle. We work with your home physician to coordinate care.

3. Cystic Fibrosis (CFTR) and Congenital Bilateral Absence of the Vas Deferens (CBAVD)

This condition arises from mutations in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator), which controls how salt and water move in and out of cells. When CFTR is faulty, body secretions become abnormally thick, affecting the lungs, digestive system, and — importantly for fertility — the male reproductive tract.

CBAVD is found in 1–2% of men with infertility and about 6% of men with obstructive azoospermia (sperm is produced normally but cannot exit the body). Nearly 95% of men with classical cystic fibrosis also have CBAVD — but the reverse is not always true: most men with isolated CBAVD do not have the full cystic fibrosis disease and are only affected in the reproductive tract. This is called the "genital-only" form of CFTR-related disease.

In these men, the testes continue to produce sperm normally, but the vas deferens — the tubes that carry sperm from the testes — are absent or blocked from birth. That is why no sperm appears in the ejaculate, even though sperm production itself is intact.

Why ethnic background matters — important information for patients:

What this means for your testing: Standard CFTR panels — the type of test used by most laboratories in Europe and North America — were designed based on Caucasian genetics and may miss important mutations in Asian and mixed-heritage patients. At SAFE Fertility Clinic, we offer extended CFTR sequencing with 5T/TG repeat analysis, which catches the full range of variants regardless of ethnic background. When CFTR testing is negative despite a CBAVD diagnosis, we also look at the ADGRG2 gene (X-linked), which is the second most common cause.

What this means for your future family

If CFTR mutations are found in the male partner, the female partner must also be tested before proceeding with ICSI. Here is why:

• Partner tests negative → Child's risk of CF is under 1 in 1,000 (about 2.5× higher than the general population, but still very low)
• Partner tests positive as a carrier → Child's risk of CF or CBAVD can be as high as 25% → We strongly recommend PGT-M (preimplantation genetic testing for monogenic disease) to select healthy embryos
• Kidney screening → 10–15% of men with CBAVD also have one missing kidney from birth (unilateral renal agenesis) — we routinely include kidney ultrasound in our evaluation

For international patients:

If you already have CFTR test results from your home country, bring them to your consultation. We will review whether the panel used covered the mutations most relevant to your ethnic background, and recommend supplementary testing only when genuinely needed.

4. Y-Chromosome Microdeletions (AZF Region)

The Y chromosome contains a critical region called AZF (Azoospermia Factor), which controls sperm production. When tiny pieces of this region are missing — a condition called microdeletions — sperm production is directly affected. This is found in approximately 10% of men with non-obstructive azoospermia and 5% of those with severely reduced sperm counts, making it the second most common genetic cause of male infertility after Klinefelter syndrome.

Not all AZF deletions are the same — and this distinction matters:

Key clinical implications you should understand:

• For complete AZFa or AZFb deletions, sperm retrieval surgery is not recommended because the chance of finding sperm is essentially zero. We understand this is difficult news, but knowing this in advance spares you from unnecessary surgery, its costs, and its emotional toll. Our team will discuss alternatives with you — including donor sperm or adoption — in a supportive, non-judgmental way.
• For AZFc deletions — by far the most common type — fatherhood through IVF/ICSI is very achievable. However, this deletion will be passed to 100% of your sons, who will face similar fertility challenges when they grow up. Before proceeding, your family should understand this and decide how to approach it — some couples choose to continue with ICSI accepting this reality; others prefer PGT-A/PGTseq-A with sex selection to have daughters instead.
• The gr/gr partial deletion has different clinical meaning in different populations. In some ethnic groups it clearly impairs fertility and slightly raises testicular cancer risk; in others it appears neutral. Our genetic counselors will interpret your result in the context of your specific background.

For international patients:

If you have had Y-microdeletion testing elsewhere, please bring the full report including which markers were tested. The EAA/EMQN 2023 guidelines updated their recommended markers, and some older tests may have missed important information.

5. Chromosomal Translocations (Balanced Reciprocal & Robertsonian)

A translocation is a genetic rearrangement where pieces of two different chromosomes have swapped places. A balanced translocation means all the genetic material is still present — just in the wrong location. Men who carry a balanced translocation are usually completely healthy and have no symptoms, but the arrangement causes problems when making sperm.

Balanced reciprocal translocations are found in approximately 1 in every 400 people in the general population and in 4–5% of couples experiencing recurrent pregnancy loss (RPL) — defined as two or more consecutive miscarriages. Robertsonian translocations (a different type) occur in about 1 in 1,000.

During sperm production, translocation carriers can produce sperm with missing or duplicated chromosomal material. When such sperm fertilize an egg, the resulting embryo cannot develop properly — leading to implantation failure or miscarriage, often early in pregnancy.

The numbers tell a clear story:

Outcome Natural conception After PGT-SR

Karyotyping identifies the hidden chromosomal cause behind failed pregnancies. PGT-SR (Preimplantation Genetic Testing for Structural Rearrangements) uses advanced NGS-based 24-chromosome screening to identify embryos that have inherited a balanced or normal chromosomal makeup — dramatically improving the odds of a healthy live birth while reducing the heartbreak of repeated miscarriage.

For international patients

A PGT-SR cycle at SAFE Fertility Clinic typically involves 2–3 weeks in Thailand for the stimulation and egg retrieval phase, followed by embryo freezing. You can return home during the 2–3 weeks needed for embryo testing, then come back for a frozen embryo transfer. Many international patients find this phased approach manageable alongside their work schedule.

Who Should Be Genetic Tested?

Based on current international guidelines (EAA, ASRM, and AUA 2024), we recommend genetic testing in the following situations:

Pre-test and post-test genetic counseling are always part of our care — particularly for Y-microdeletions (because they are passed to 100% of sons) and for CFTR (because your partner's status and your future children are involved).

Why Early Genetic Testing Changes Everything

Genetic abnormalities cannot be detected from how a man looks, feels, or performs. Many of the men we meet have been told their entire lives that they are perfectly healthy — and they are — until the moment they try to start a family.

Genetic testing before you begin treatment offers you:

• Targeted, evidence-based treatment — avoiding paths that cannot succeed (for example, surgery that has no realistic chance of retrieving sperm) and choosing paths that genuinely can help
• Honest, realistic expectations before you commit time, travel, and financial resources to ART — we believe you deserve to know the real numbers, not optimistic ones
• Protection for your future children — through preimplantation genetic testing (PGT-M, PGT-SR) or, where appropriate, donor gametes
• Comprehensive genetic counseling that considers both you and your partner, and addresses decisions that extend into the future

SAFE Fertility Clinic, located in the heart of Bangkok, has been caring for couples from Thailand and around the world since 2007. We are one of Southeast Asia's most established reproductive medicine centers and a leading destination for medical travelers seeking IVF, ICSI, and advanced genetic screening in a clinical environment that meets the highest international standards.

Our genetic services include:

• Karyotyping (G-banding, 30+ metaphases; 100 metaphases where mosaicism is suspected)
• Y-chromosome microdeletion analysis using EAA/EMQN 2023 recommended markers
• Comprehensive CFTR sequencing including 5T/TG repeat analysis (adapted for Asian and mixed-heritage patients)
• PGT-M (single gene disorders), PGT-SR (structural rearrangements), and PGT-A/PGTseq-A (aneuploidy screening)
• Pre-test and post-test counseling by certified Genetic Counselors
• Integrated care planning with board-certified reproductive endocrinologists and andrologists
• Sperm retrieval: PESA, TESA, and micro-TESE
• Advanced sperm selection: MACS, IMSI by Leica, in our international-standard ART laboratory

For international patients, we offer:

• English-speaking reproductive endocrinologists, genetic counselors, and nursing staff
• Integrated care coordination with your home physician for before-and-after treatment continuity
• Review of genetic and fertility records from your home country prior to your first visit
• Flexible treatment timing including split-cycle protocols for travelers who cannot stay continuously
• Assistance with accommodation, airport transfer, and translation services

Article by: Nattharut Kulphaweesuwan, M.D. (Dr.Kong)

SAFE Fertility Group PCL, Gaysorn Amarin Branch

Medical License Number 37453