[Genetic Counselor]

Understanding the Genetic Causes of Male Infertility

[Genetic Counselor]

Klinefelter Syndrome

[Genetic Counselor]

Understanding the Genetic Causes of Male Infertility

[Genetic Counselor]

First trimester screening is a set of tests done early in pregnancy, usually between 11 and 14 weeks, to estimate the chance that the baby has certain chromosome conditions.
Chromosomes are the packages that carry our DNA. Most people have 46 chromosomes in each cell, arranged in 23 pairs. Sometimes a baby has an extra copy of one chromosome, which is called a trisomy. First trimester screening looks mainly for three of these:

• Down syndrome (trisomy 21) An extra copy of chromosome 21. It is the most common chromosome condition in babies born alive. It causes learning disability of varying degree, and some babies have heart or bowel differences.
• Edwards syndrome (trisomy 18) An extra copy of chromosome 18. It causes serious problems with the heart and other organs, and many pregnancies do not continue to birth.
• Patau syndrome (trisomy 13) An extra copy of chromosome 13. Like Edwards syndrome, it is usually very serious.

Any pregnancy can be affected. These changes usually happen by chance when the egg or sperm is formed, and not because of anything the parents did. The chance does rise with the mother’s age. At age 20, the chance of Down syndrome at birth is about 1-in-1,250. At age 40, it is about 1-in-86. This is why professional guidelines, including those of the American College of Obstetricians and Gynaecologists, recommend offering screening to every pregnant person, whatever their age.

The scan part of the test can also give early clues about other conditions, such as Turner syndrome (a missing X chromosome in a girl), triploidy (a full extra set of chromosomes), and some heart and skeletal conditions.

It is important to know what first trimester screening is not. It is a screening test, not a diagnosis. It gives a chance, not a yes or no answer. It also does not check for single-gene conditions such as beta-thalassemia, sickle cell disease, or spinal muscular atrophy. Those need separate carrier screening of the parents.

[Genetic Counselor]

First trimester screening combines three pieces of information. This is why it is often called the “combined test”. In India, the blood test part is commonly called the “double marker” test.

• The nuchal translucency scans an ultrasound scan measures a small pocket of fluid at the back of the baby’s neck, called the nuchal translucency. All babies have some fluid here. Babies with chromosome conditions tend to have more. The scan must be done when the baby measures between 45 and 84 millimetres from head to bottom, which is roughly 11 weeks to 13 weeks and 6 days. It needs a trained and certified sonologist because a difference of a fraction of a millimetre changes the result. The scan also checks the baby’s heartbeat, confirms the due date, counts the babies, and looks at early body structure.
• The blood test A sample of the mother’s blood is checked for two pregnancy hormones: free beta human chorionic gonadotropin and pregnancy-associated plasma protein A. In Down syndrome, the first is often higher than usual and the second is often lower.
• The mother’s age and details Age, weight, number of babies, and some other factors are added in.

A computer program combines all three to give a single number for each condition, such as “1-in-2,500” or “1-in-150”. This means that out of 2,500 (or 150) pregnancies with the same result, 1 baby would be expected to have the condition. Each laboratory uses a cut-off, often around 1-in-250 or 1-in-300. A number with a smaller chance than the cut-off is reported as “low risk”. A number with a higher chance is reported as “high risk” or “increased chance”.

Combined screening finds about 82 to 87 of every 100 babies with Down syndrome, while flagging about 5 in every 100 pregnancies overall as high risk. A low-risk result is reassuring, but it does not rule out a chromosome condition completely.

[Genetic Counselor]

No. A high-risk result means the chance is higher than the laboratory’s cut-off. It does not mean the baby has the condition. Because the test flags about 5 in every 100 pregnancies, and chromosome conditions are much less common than that, most pregnancies with a high-risk result turn out to have a baby with normal chromosomes. It is natural to feel frightened. The next step is to get clear answers, not to decide straight away.

• Meet a genetic counselor or clinical geneticist They will explain what your specific number means, since a result of 1-in-10 is very different from 1-in-200. They will also review the scan findings and your family history.
• Option 1: Non-Invasive Prenatal Testing This is a more accurate screening test that looks at small fragments of the baby’s DNA (from the placenta) in the mother’s blood. It carries no risk to the pregnancy. It is still a screening test, so a high-risk result from it also needs confirmation.
• Option 2: Diagnostic testing This gives a definite answer by testing the baby’s own cells. Chorionic villus sampling takes a tiny sample of the placenta, usually at 11 to 14 weeks. Amniocentesis takes a small amount of the fluid around the baby, from 15 weeks onwards. Both carry a small chance of miscarriage, which should be weighed against the chance found on screening and what the answer would mean for your family.
• What the laboratory tests for the sample is usually checked for the common trisomies, often with a rapid test. When the scan shows a thick nuchal translucency or a structural difference, guidelines recommend a chromosomal microarray. This test looks for small missing or extra pieces of chromosomes that a standard chromosome study can miss.

Some families choose further testing to prepare. Others choose not to test at all. Both are valid choices, and your care team should support whichever path you take.

[Genetic Counselor]

This is one of the most common reasons families are referred to a genetics clinic after first trimester screening. The American College of Obstetricians and Gynaecologists considers a nuchal translucency of 3.0 millimetres or more, or above the 99th percentile for the baby’s size, as increased. At this level, genetic counseling and diagnostic testing should be offered, even if the blood test and overall risk number look reassuring.

A thick nuchal translucency is not only linked to the common trisomies. It can also be an early sign of:

• Smaller chromosome changes for example, 22q11.2 deletion syndrome, which can affect the heart, immune system, and learning. These are found by chromosomal microarray.
• Single-gene conditions the best known are the RASopathies, a group that includes Noonan syndrome. These are caused by changes in genes such as PTPN11, SOS1, RAF1, and RIT1, and can affect the heart, growth, and development.
• Heart and skeletal differences Some babies with thick nuchal translucency have a heart condition or a skeletal dysplasia, a condition affecting bone growth.

When the chromosomes and microarray are normal, some centres offer a RASopathy gene panel or exome sequencing, which reads most of the baby’s genes at once. A 2023 review combining eight studies found that about 8 in every 100 babies with an isolated thick nuchal translucency and normal chromosome tests had a genetic diagnosis on exome sequencing. When the later anatomy scan was completely normal, this fell to about 4 in every 100. The chance of finding something rises as the measurement gets thicker.

There is also good news. Research shows that if the chromosome tests are normal and a detailed anatomy scan at 18 to 22 weeks shows no problems, the chance of a healthy baby is close to that of any other pregnancy. A detailed heart scan, called a fetal echocardiogram, is also usually advised. Most babies in this situation are born healthy.

[Genetic Counselor]

Both are valid options, and the right choice depends on cost, access, timing, and what you want to know.

• Non-Invasive Prenatal Testing This is the most accurate screening test for Down syndrome, Edwards syndrome, and Patau syndrome. It finds about 99 in every 100 babies with Down syndrome and gives far fewer false alarms than the combined test. It can be done from 10 weeks. It is more expensive, and sometimes returns a “no result”, which itself needs follow-up. The Society for Maternal-Fetal Medicine does not recommend routine screening for rare microdeletions with this test, because false alarms are more common. Screening for sex chromosome differences should be optional. Under Indian law, the baby’s sex is not disclosed.
• First trimester combined screening This is less expensive and widely available. It detects fewer affected babies and has more false alarms. Its big advantage is the nuchal translucency scan, which can pick up early signs of heart, skeletal, and other genetic conditions that blood tests alone cannot.

Guidelines advise choosing one screening approach rather than doing several and combining them. Even if you choose Non-Invasive Prenatal Testing, the 11 to 14 week scan is still valuable for checking the baby’s early structure, although the nuchal translucency measurement adds nothing extra for Down syndrome risk once Non-Invasive Prenatal Testing has been done.

Everyone needs to know that neither test can replace:
• Diagnose a condition Only chorionic villus sampling or amniocentesis can confirm a result.
• Check for single-gene conditions Beta-thalassemia, sickle cell disease, spinal muscular atrophy, and cystic fibrosis need carrier screening of the parents, ideally before or early in pregnancy.
• Replace the anatomy scan All pregnancies should have a detailed scan at 18 to 22 weeks.

Many people first see a doctor after 14 weeks. If you have missed the window for first trimester screening, second trimester blood screening or Non-Invasive Prenatal Testing are still available. A consultation with a clinical geneticist can help you decide which fits your pregnancy best.

[Genetic Counselor]

The outlook for cystic fibrosis has improved enormously. A few decades ago, most children with the condition did not reach adulthood. Today, in countries with early diagnosis and full access to care, people with cystic fibrosis commonly study, work, marry, and have families. The Cystic Fibrosis Foundation Patient Registry in the United States reports that people born between 2020 and 2024 have a predicted median survival of about 65 years, a gain of nearly two decades compared with only a few years earlier. Much of this improvement is linked to CFTR modulator medications.

Outcomes depend heavily on how early the condition is diagnosed and how consistently care is given. In India, studies have shown that late diagnosis, severe malnutrition at diagnosis, and early Pseudomonas infection are linked with poorer outcomes. This is why early testing of children with suggestive symptoms, and regular follow-up at an experienced center, make such a difference.

Most men with cystic fibrosis are infertile because the tubes that carry sperm are missing, but they still produce sperm, and many become fathers with assisted reproduction. Women may have slightly reduced fertility but can often become pregnant, ideally with planning alongside their care team.

Regular monitoring helps catch problems early:
• Clinic visits Monthly in early infancy, then about every 3 months from early childhood onward, to review breathing, growth, and nutrition.
• Lung function and infection checks Breathing tests from about 5 years of age, sputum or throat cultures at least every 3 months to detect new infections, and chest imaging about every 2 years.
• Nutrition and blood tests Yearly blood tests to check vitamin levels, liver function, and blood counts.
• Diabetes screening A yearly glucose tolerance test from about 10 years of age.
• Bone health Bone density scans from late childhood or adolescence, since bone thinning is common.
• Emotional wellbeing Yearly screening for anxiety and depression in older children, adults, and caregivers, since living with a lifelong condition can be demanding.

With early diagnosis, dedicated daily care, and access to modern treatments, many people with cystic fibrosis now live long, full lives.

[Genetic Counselor]

There is no cure yet, but treatment has changed dramatically over the past decade. Care now has two parts: treating the effects of thick mucus, and, for many people, treating the faulty CFTR protein itself.

• Airway clearance every day Chest physiotherapy, breathing techniques, and devices that help loosen mucus are the backbone of lung care. Families are taught to do this at home, usually once or twice daily. Regular physical activity also helps clear the airways.
• Inhaled medications Salt-water (hypertonic saline) inhalations and a medication called dornase alfa help thin the mucus so it is easier to cough up. Inhaled antibiotics are used for people with long-term Pseudomonas infection.
• Antibiotics for infections Chest infections are treated early and firmly, by mouth, by inhalation, or through a vein in hospital, to limit lasting lung damage.
• Pancreatic enzyme capsules and nutrition People whose pancreas does not work take enzyme capsules with every meal and snack to digest food. A high-calorie diet, extra salt (especially in hot weather), and supplements of vitamins A, D, E, and K are also part of routine care.
• CFTR modulator medications These tablets work directly on the faulty CFTR protein, helping it fold correctly, reach the cell surface, or open properly. The most widely used combination, elexacaftor with tezacaftor and ivacaftor, can markedly improve lung function, weight, and quality of life, and in the United States it is now approved from 2 years of age. A newer once-daily combination, vanzacaftor with tezacaftor and deutivacaftor, is approved from 6 years of age. Whether these medicines will work depends on the person’s specific CFTR changes, which is one reason genetic testing is so important. In India, access to these medications remains limited and expensive, and families should discuss current options with their treating team.
• Treating complications Diabetes related to cystic fibrosis, liver disease, and bone thinning are treated as they arise. For people with advanced lung disease, lung transplantation may be considered.

Care works best through a specialized cystic fibrosis team, including a lung specialist, dietitian, physiotherapist, and genetic counselor, working together over the long term.

[Genetic Counselor]

Yes. Cystic fibrosis is inherited in an autosomal recessive pattern. This means a person must inherit a disease-causing change in both copies of the CFTR gene, one from each parent, to have the condition.

A person with one changed copy and one working copy is called a carrier. Carriers are healthy and usually do not know their status until a relative is diagnosed or they are tested. When both parents are carriers, each pregnancy has:

• a 1-in-4 chance that the child inherits two changed copies and has cystic fibrosis
• a 1-in-2 chance that the child inherits one changed copy and is a healthy carrier
• a 1-in-4 chance that the child inherits two working copies and is neither affected nor a carrier

These chances apply to every pregnancy separately. Having one affected child does not mean the next three will be unaffected, much like tossing a coin does not “remember” the last toss.
Healthy brothers and sisters of a child with cystic fibrosis have a 2-in-3 chance of being carriers. This becomes important when they plan their own families. Aunts, uncles, and cousins may also be carriers, so testing is often offered to the wider family once the exact CFTR changes are known. This approach is called cascade testing.

Cystic fibrosis is most common among people of Northern European ancestry, where about 1 in 25 people is a carrier. It was long believed to be rare in India, but research now suggests it is underdiagnosed rather than truly rare. Estimates of how often it occurs among Indian births range widely, from about 1 in 2,500 to 1 in 40,000, largely because many affected children are never tested. The F508del change accounts for a much smaller share of disease-causing changes in Indian patients than in European patients, which is why full gene sequencing is preferred here.
For couples who are both known carriers, options include testing during pregnancy through chorionic villus sampling or amniocentesis, and preimplantation genetic testing alongside in vitro fertilization, which allows embryos to be tested before a pregnancy begins. Carrier screening before pregnancy is also offered to couples without a family history. A genetic counselor can explain which options suit a family’s situation and values.

[Genetic Counselor]

Cystic fibrosis looks different from person to person, but symptoms often appear in infancy or early childhood. In India, children are frequently diagnosed later than in countries with newborn screening, often after several years of repeated infections and poor growth, so recognizing the early signs matters.

• Lungs and sinuses A persistent cough, wheezing, and repeated chest infections or pneumonia that keep coming back. Over time, lung infections with bacteria such as Pseudomonas become common. Blocked sinuses and nasal polyps may also develop.
• Digestion and growth In about 85 out of 100 people with cystic fibrosis, the pancreas cannot release the enzymes needed to digest food. This leads to large, greasy, foul-smelling stools, a swollen belly, and poor weight gain despite a good appetite. Some newborns are born with a blocked bowel, called meconium ileus, which may be the very first sign.
• Salty skin and salt loss Parents sometimes notice their baby tastes salty when kissed. In hot climates such as much of India, children can lose so much salt in sweat that they become dehydrated and unwell, sometimes with dangerously low salt levels in the blood.
• Liver and other organs A smaller number of children develop liver problems, and diabetes related to cystic fibrosis becomes more common in the teenage and adult years.

Diagnosis rests on two things: a clinical reason to suspect cystic fibrosis (symptoms, a positive newborn screen, or a family history) and a test proving the CFTR gate is not working.

• Sweat chloride test This remains the main diagnostic test. A small, painless patch on the arm collects sweat, which is then measured for salt. A level of 60 millimoles per liter or higher confirms cystic fibrosis. A level between 30 and 59 is borderline and needs further testing. Few centers in India offer this test, so families may need a referral to a specialized hospital.
• Genetic testing of the CFTR gene Finding a disease-causing change in both copies of the gene confirms the diagnosis. Because the CFTR changes seen in Indian families are highly varied and often differ from those common in Europe, full sequencing of the gene is usually more reliable than a small panel of common variants.
• Newborn screening Many countries test all babies using a blood spot that measures a pancreatic protein called immunoreactive trypsinogen. Routine newborn screening for cystic fibrosis is not yet part of standard programs across India, which is one reason diagnosis is often delayed here.

[Genetic Counselor]

Cystic fibrosis is a genetic condition that makes the body produce thick, sticky mucus instead of the thin, slippery mucus that normally lines and protects many organs. This thick mucus builds up and blocks passageways in the lungs, the pancreas, the liver, the intestines, and the reproductive tract. Over time, these blockages cause repeated chest infections, trouble digesting food, and damage to several organs.

The cause lies in a single gene called CFTR. This gene carries the instructions for building a protein that sits on the surface of cells and works like a tiny gate, letting salt (chloride) and water move in and out of the cell. When this gate works properly, the right amount of water flows into the mucus and keeps it thin. When both copies of the CFTR gene carry a pathogenic variant, meaning a harmful change, the gate is missing, faulty, or stays shut. Salt and water get trapped inside the cells, and the mucus outside becomes dry, thick, and hard to clear.

More than 2,000 different changes in the CFTR gene have been described, though not all of them cause disease. They affect the gate in different ways. Some changes stop the protein from being made at all. Others produce a protein that is folded incorrectly and never reaches the cell surface; the most common change worldwide, called F508del, works this way. Still others let the protein reach the surface but leave the gate unable to open properly. This matters for families because the specific changes a person carries help predict how severe the condition may be and, importantly, which newer medications are likely to work.

The same faulty gate also explains a well-known sign of the condition: sweat that is unusually salty. In sweat glands, the CFTR protein normally pulls salt back into the body. When it does not work, too much salt is lost in sweat, which is the basis of the sweat test used for diagnosis.

Cystic fibrosis is not caused by anything a parent did during pregnancy, and it is not contagious. It results entirely from the combination of CFTR gene copies a child inherits from each parent.

[Genetic Counselor]

Cascade testing is the process of offering genetic counseling and testing to the blood relatives of a person who has been found to carry a disease-causing genetic change. The first person in the family to be diagnosed is called the index patient. Once the exact genetic change in the index patient is known, relatives can be checked for that one specific change. The testing then “cascades” outward through the family: first to the closest relatives, and then, for anyone who also tests positive, on to their own close relatives.

The reason this matters is simple. You share part of your DNA with your parents, brothers and sisters, and children. If you carry a genetic change that raises the risk of a serious condition, some of them may carry it too, often without knowing. For many conditions, knowing early changes what happens next. A relative who carries a hereditary cancer gene change can begin earlier or more frequent screening. A relative with familial hypercholesterolemia, an inherited cause of very high cholesterol, can start treatment years before a heart attack. A couple who both carry beta-thalassemia can plan a pregnancy with full information.

The Centers for Disease Control and Prevention in the United States lists three groups of conditions where cascade testing has the strongest evidence of saving lives: hereditary breast and ovarian cancer (BRCA1 and BRCA2), Lynch syndrome (a hereditary colon and womb cancer condition), and familial hypercholesterolemia. But the same approach applies to many other conditions, including thalassemia, Duchenne muscular dystrophy, inherited heart rhythm and heart muscle conditions, and Fragile X syndrome.

Cascade testing is also efficient. An Indian study of beta-thalassemia families found that testing the relatives of affected children identified carriers at 5 to 6 times the rate of general population screening. Relatives of a known patient are simply much more likely to carry the same change than a random person.

Your doctor is not asking you to test your family. They are asking you to let your family know that an option exists, so each relative can decide for themselves.

[Genetic Counselor]

In general, cascade testing starts with first-degree relatives: parents, brothers and sisters, and children. Each of these relatives shares about half of your DNA. If a first-degree relative has died or cannot be reached, testing moves to second-degree relatives: grandparents, aunts and uncles, nieces and nephews, and half-siblings. When a relative tests positive, their own first-degree relatives are then offered testing, and so on through the family.

Exactly who is at risk depends on how the condition is inherited.
• Autosomal dominant conditions One copy of the changed gene is enough to raise risk. Examples include BRCA1 and BRCA2, Lynch syndrome, and familial hypercholesterolemia. Each child of a carrier has a 1-in-2 chance of inheriting the change, and each brother or sister usually has a 1-in-2 chance too. One side of the family usually carries it, and testing parents can show which side.
• Autosomal recessive conditions A person is affected only if they inherit a changed copy from both parents. Examples include beta-thalassemia, sickle cell disease, and spinal muscular atrophy. Both parents of an affected child are usually carriers. Each brother or sister of an affected child has a 2-in-3 chance of being a carrier if they are unaffected. Aunts, uncles, and cousins on both sides may also be carriers. For these families, cascade testing is mainly about identifying carriers before they plan their own pregnancies, and testing their partners.
• X-linked conditions The changed gene sits on the X chromosome. Examples include Duchenne muscular dystrophy and Fragile X syndrome. Females in the mother’s line, such as sisters, maternal aunts, and female cousins, may be carriers and can have affected sons. Their carrier status matters for pregnancy planning and, in some conditions, for their own health.

A genetic counselor will usually draw a family tree with you. This shows exactly which relatives are at risk, how high their chance is, and which order makes the most sense, including which relatives to prioritize because they are of an age where screening or prevention would already apply.

[Author]

Posts