Rare Diseases

In the UK, a rare disease is defined as a condition that affects fewer than 1 in 2,000 people in the general population, following the definition used across the European Union. Individually each condition is uncommon, but there are thought to be between 6,000 and 8,000 different rare diseases, so as a group they affect a significant number of families. Many have a genetic cause and are present from birth.

Although any single rare disease is unlikely, screening in pregnancy can offer reassurance or early information where it is wanted. Our genetic testing and counselling service can explain which conditions different tests do and do not cover, and our extended SMART Test NIPT screens for a wide range of chromosomal and single-gene conditions. If a rare disease runs in your family, our specialists can help you decide what testing, if any, is right for you.

In 2023, the England Rare Diseases Action Plan underscores the importance of newborn screening for rare genetic conditions. The NHS is strongly supporting the development of a comprehensive whole genome sequencing (WGS) research study, with the aim of screening newborns for up to 200 rare genetic conditions. Early intervention can profoundly enhance outcomes for these infants.

Rare diseases are often called “orphan diseases” due to the lack of attention and resources they historically received. These conditions were “orphans” because they were neglected, with limited research, funding, and pharmaceutical development. In many cases, rare diseases did not attract the interest of pharmaceutical companies or researchers because they affected such a small number of people. As a result, patients with rare diseases often felt “orphaned” by the healthcare system, lacking proper diagnosis, treatment, and support.

To address this issue, governments and organizations worldwide have taken steps to provide more attention and resources to rare diseases. Laws like the Orphan Drug Act in the United States offer incentives to develop treatments for these conditions. Despite this progress, the term “orphan disease” continues to be a historical reference to the lack of attention these conditions once received.

Yes. Rare diseases contribute significantly to infant mortality and lifelong disability. To enhance outcomes, timely diagnosis and effective treatments are essential. Genomic sequencing has revolutionized conventional diagnostic procedures, offering swift, precise, and cost-effective genetic diagnoses to a broader spectrum of individuals. This advancement plays a pivotal role in addressing the challenges of rare diseases.

The proportion of rare diseases that affect children is the majority. Around 75 per cent of rare diseases are thought to impact children, and collectively they contribute to nearly one-third of infant mortality in the UK, as highlighted in the 2023 England Rare Diseases Action Plan. Many are present from birth, which is why early screening and diagnosis matter so much.

Because so many rare conditions begin in childhood, screening during pregnancy can help you prepare and plan care in good time. Our SMART Test scan and NIPT package combines an advanced early anomaly scan with extended non-invasive prenatal testing, and our genetic counselling service can help you understand what any results mean for your family. If you have specific concerns, our specialists are here to talk them through with you.

The Newborn Blood Spot NHS Screening Programme plays a crucial role in the early identification, referral, and treatment of babies with nine rare yet serious conditions:

This screening program is a vital component of healthcare, ensuring early intervention and support for infants at risk of these conditions.

It’s essential to recognise that the vast majority of these conditions cannot be detected through prenatal ultrasound screenings.

Currently, only cystic fibrosis and sickle cell anaemia have the option of non-invasive prenatal testing (NIPT) through tests like SMART TEST or UNITY Complete. These advanced genetic screenings provide a unique opportunity to identify these conditions and plan for the best care possible during pregnancy and after birth

• sickle cell disease (SCD)
• cystic fibrosis (CF)
• congenital hypothyroidism (CHT)
• phenylketonuria (PKU)
• medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
• maple syrup urine disease (MSUD)
• isovaleric acidaemia (IVA)
• glutaric aciduria type 1 (GA1)
• homocystinuria (HCU)

The commonest rare diseases for newborns include:

Prenatal or newborn screening for these conditions is vital for early diagnosis and timely intervention, which can significantly improve outcomes.

• cystic fibrosis
• sickle cell disease
• DiGeorge syndrome
• Noonan syndrome
• Turner syndrome
• Klinefelter syndrome

Taken together as a group, de novo mutations are more common than Down’s syndrome. Down’s syndrome (trisomy 21) is a single, relatively frequent condition, occurring in roughly 1 in 700 births. De novo mutations, by contrast, are new genetic changes that arise spontaneously rather than being inherited, and as a whole family of rare conditions they collectively account for a larger number of affected pregnancies.

This matters because standard first-line screening focuses on the common trisomies, so many de novo conditions fall outside it. Our extended SMART Test NIPT looks for a much broader range of genetic conditions alongside Down’s syndrome, and our team can help you weigh up which level of testing suits you. This information is for general education only; please speak to our specialists or your midwife about your individual situation.

Diagnosing a rare disease in a fetus or newborn typically involves a series of medical assessments and tests to determine the specific condition.

The diagnostic process varies depending on the symptoms and clinical findings. It’s important to work closely with healthcare professionals, including genetic specialists and paediatricians, to determine the most appropriate diagnostic approach for your child. Early diagnosis is crucial to ensure timely intervention and management of rare diseases in newborns or during pregnancy.

• Prenatal Screening: Sometimes, during routine prenatal check-ups and ultrasound scans, doctors may notice certain signs that suggest a rare disease in the developing fetus. These signs could include physical abnormalities or issues related to the baby’s growth.
• Genetic Testing: In cases where there is a suspicion of a rare genetic condition, healthcare professionals may recommend genetic tests like amniocentesis or chorionic villus sampling (CVS). These tests examine the DNA of the developing baby to identify any chromosomal or genetic abnormalities.
• Newborn Screening: After birth, newborns undergo a set of tests known as newborn screening. These tests are designed to detect common genetic and metabolic disorders. Some of these conditions may be rare but are included in the screening to ensure early diagnosis and prompt treatment.
• Clinical Assessment: For some rare diseases, doctors may rely on a comprehensive clinical evaluation. This involves a detailed review of the baby’s medical history, a physical examination, and an assessment of any symptoms or signs that could indicate a rare condition.
• Advanced Genetic Testing: To pinpoint the exact rare disease, advanced genetic tests may be necessary. These tests involve detailed examination of the baby’s DNA, such as DNA sequencing, chromosomal microarray analysis, or whole exome sequencing, to identify the specific genetic mutation responsible for the condition. Extended Non-Invasive Prenatal Testing (NIPT) can spot some rare diseases.

Ultrasound scans, both screening scans and targeted (expert) scans, can be valuable tools in the diagnosis and monitoring of rare conditions, especially during pregnancy. Screening scans check the baby’s health. Targeted scans look closely to find specific rare disorders. Here’s an explanation of how these scans can assist in the diagnosis of rare diseases:

Screening Ultrasound Examination: A screening ultrasound examination is a standard procedure during pregnancy and is typically performed as part of routine prenatal care. It helps detect common and, in some cases, rare conditions by providing detailed images of the developing fetus. Examples of how it can assist in the diagnosis of rare conditions include:

Target (Expert) Ultrasound Examination: In cases where a rare condition is suspected or there is a family history of a specific condition, healthcare providers may recommend a more specialized or expert ultrasound examination. This examination is performed by a Fetal Medicine Specialist with expertise in identifying rare conditions. Examples include:

In summary, both screening and expert ultrasound examinations play important roles in the diagnosis of rare conditions during pregnancy. While screening ultrasounds provide a general overview of fetal health and can raise suspicions of rare diseases, expert ultrasounds offer a more specialized and detailed assessment, often involving specific organ systems or anatomical areas to confirm or rule out the presence of rare syndromes.

• Structural Abnormalities: A screening ultrasound can reveal structural abnormalities, such as heart defects or brain anomalies, which may be indicative of a rare condition. For instance, an ultrasound might show signs of DiGeorge syndrome, a genetic disorder associated with heart defects and developmental challenges.
• Growth Issues: Slower than expected fetal growth may be an early sign of certain rare conditions. An ultrasound can monitor the baby’s growth, helping to detect conditions like intrauterine 0r fetal growth restriction (IUGR or FGR), which can be associated with rare genetic syndromes.
• Chromosomal Disorders: Some rare genetic conditions are associated with specific physical features that can be detected through ultrasound. For example, certain chromosomal disorders might result in facial abnormalities that can be observed during an ultrasound examination.
• Advanced Cardiac Ultrasound: An expert ultrasound examination of the fetal heart, often known as a fetal echocardiogram, can be used to detect rare cardiac anomalies that might not be apparent in a standard screening ultrasound. This is crucial for diagnosing conditions like hypoplastic left heart syndrome.
• Genetic Syndromes: Fetal Medicine Specialists can focus on specific features associated with certain rare genetic syndromes. For instance, in cases where a parent has a known rare genetic syndrome, an expert ultrasound might look for signs of the same condition in the developing fetus.
• Detailed Anatomical Scans: An expert ultrasound can provide a more detailed assessment of specific fetal structures, helping identify anomalies associated with rare conditions. For example, it can detect brain abnormalities in holoprosencephaly, a rare neural development disorder.

De novo mutations are changes in a person’s DNA that are not inherited from their parents. Instead, they are new mutations that occur for the first time in the affected individual. These mutations can happen during the formation of an individual’s egg or sperm cells or early in the development of the embryo.

Key points:

Not Inherited from Parents: De novo mutations are not passed down from the parents but arise spontaneously in the affected person’s genetic code.

Occurrence: They can occur during the creation of an individual’s egg or sperm cells or at the very early stages of embryonic development.

Role in Rare Diseases: De novo mutations are often associated with certain rare genetic disorders, as they can introduce genetic changes that cause health problems or developmental conditions in the affected individual.

Genetic Testing: Identifying de novo mutations is essential for understanding the genetic basis of rare conditions and may be crucial for diagnosis and genetic counselling.

In summary, de novo mutations are new genetic changes that are not inherited and play a significant role in developing certain rare diseases and conditions.

• Not Inherited from Parents: De novo mutations are not passed down from the parents but arise spontaneously in the affected person’s genetic code.
• Occurrence: They can occur during the creation of an individual’s egg or sperm cells or at the very early stages of embryonic development.
• Role in Rare Diseases: De novo mutations are often associated with certain rare genetic disorders, as they can introduce genetic changes that cause health problems or developmental conditions in the affected individual.
• Genetic Testing: Identifying de novo mutations is essential for understanding the genetic basis of rare conditions and may be crucial for diagnosis and genetic counselling.

Yes, de novo mutations can occur in families with no prior history of the disease or condition. They may occur in babies of parents with healthy lifestyles. These mutations are entirely random and not inherited from either parent. De novo mutations can arise during the formation of a person’s egg or sperm cells or in the early stages of embryo development.

Key points:

Random Events: De novo mutations are spontaneous and unexpected events in the genetic code. They can affect anyone, even if their parents are healthy and have no family history of the disease.

Unpredictable: The occurrence of de novo mutations is unpredictable and not related to the health or genetics of the parents. It’s a chance event.

Role in Rare Diseases: De novo mutations are often associated with rare genetic diseases because they can introduce genetic changes that cause health problems or developmental conditions in the affected individual.

Genetic Counseling: In cases where a de novo mutation leads to a rare genetic condition, genetic counselling can help families understand the implications and risks of future pregnancies.

In summary, de novo mutations can happen in individuals with healthy parents and no family history of the disease. These random and unpredictable mutations play a role in the development of certain rare genetic diseases.

• Random Events: De novo mutations are spontaneous and unexpected events in the genetic code. They can affect anyone, even if their parents are healthy and have no family history of the disease.
• Unpredictable: The occurrence of de novo mutations is unpredictable and not related to the health or genetics of the parents. It’s a chance event.
• Role in Rare Diseases: De novo mutations are often associated with rare genetic diseases because they can introduce genetic changes that cause health problems or developmental conditions in the affected individual.
• Genetic Counseling: In cases where a de novo mutation leads to a rare genetic condition, genetic counselling can help families understand the implications and risks of future pregnancies.

NIPT (Non-Invasive Prenatal Testing) for single gene (monogenic) disorders aims to detect specific genetic mutations in the developing fetus by analyzing a blood sample from a healthy mother.

Genetic Mutation Detection: This type of NIPT focuses on identifying single gene de novo mutations in the developing fetus. These mutations can lead to severe genetic disorders, even if the mother is healthy.

Parental Genetic Information: While the mother is healthy, the concern is that her egg or sperm cell may carry a de novo mutation. This mutation is rare and not present in either parent’s DNA, but it can occur during the formation of the egg or sperm.

Fetal DNA in Maternal Blood: During pregnancy, small amounts of fetal DNA from the developing baby naturally enter the mother’s bloodstream. NIPT takes advantage of this to analyze the fetal DNA for the presence of specific de novo mutations.

Advanced Genetic Sequencing: Highly sophisticated genetic sequencing techniques are used to examine the fetal DNA in the mother’s blood. This allows scientists to search for the particular genetic mutation that causes the monogenic disorder.

Early Detection: NIPT for single gene mutations is performed during pregnancy, providing an early and non-invasive way to detect these serious genetic conditions. Early detection is crucial for preparing for the baby’s health needs.

Family History and Risk Assessment: This test is especially important for families with a known history of single gene disorders or when there’s a concern about the potential for a de novo mutation (for example, advanced paternal age).

Counselling and Support: If the test detects a de novo mutation, healthcare providers can offer genetic counselling and support for the family. This guidance helps the family understand the condition and prepares them for the baby’s care.

In summary, NIPT for single gene (monogenic) disorders uses advanced genetic sequencing to examine fetal DNA in the mother’s blood. This technology helps identify rare de novo mutations that can lead to serious genetic conditions, even when the parents are healthy. Early detection and preparation are essential for managing these conditions.

• Genetic Mutation Detection: This type of NIPT focuses on identifying single gene de novo mutations in the developing fetus. These mutations can lead to severe genetic disorders, even if the mother is healthy.
• Parental Genetic Information: While the mother is healthy, the concern is that her egg or sperm cell may carry a de novo mutation. This mutation is rare and not present in either parent’s DNA, but it can occur during the formation of the egg or sperm.
• Fetal DNA in Maternal Blood: During pregnancy, small amounts of fetal DNA from the developing baby naturally enter the mother’s bloodstream. NIPT takes advantage of this to analyze the fetal DNA for the presence of specific de novo mutations.
• Advanced Genetic Sequencing: Highly sophisticated genetic sequencing techniques are used to examine the fetal DNA in the mother’s blood. This allows scientists to search for the particular genetic mutation that causes the monogenic disorder.
• Early Detection: NIPT for single gene mutations is performed during pregnancy, providing an early and non-invasive way to detect these serious genetic conditions. Early detection is crucial for preparing for the baby’s health needs.
• Family History and Risk Assessment: This test is especially important for families with a known history of single gene disorders or when there’s a concern about the potential for a de novo mutation (for example, advanced paternal age).
• Counselling and Support: If the test detects a de novo mutation, healthcare providers can offer genetic counselling and support for the family. This guidance helps the family understand the condition and prepares them for the baby’s care.

The SMART TEST is designed to help parents identify rare diseases more effectively. Here’s a simplified explanation for parents:

Advanced Ultrasound Scan: The SMART TEST begins with an advanced ultrasound scan that carefully examines your developing baby’s physical features. The scan looks for specific anomalies or unusual physical traits that might be associated with genetic diseases. This step provides valuable insights into your baby’s health.

Cell-Free Fetal DNA Analysis: The SMART TEST includes a unique analysis of cell-free fetal DNA. This DNA is naturally present in the mother’s blood and contains information about the baby’s genetic makeup. The analysis identifies relatively common monogenic (single-gene) disorders the baby might acquire de novo or inherit.

Combining the information from the ultrasound scan and the genetic analysis, the SMART TEST aims to provide a comprehensive assessment of your baby’s health, helping you and your healthcare team make informed decisions about your pregnancy and prepare for any potential healthcare needs. It’s an essential tool for the early detection and understanding of rare diseases that might affect your child.

The SMART TEST is a valuable tool in assessing your baby’s health, but it’s important to note that it cannot diagnose or exclude all genetic diseases, even very severe ones. It focuses on specific anomalies and relatively common monogenic (single-gene) disorders, providing important insights but not covering every possible genetic condition.

Yes, the phenomenon is known as the “paternal age effect.” Fathers older than 40 years are at an increased risk of having children with de novo mutations for several reasons:

As people get older, the genetic material in their sperm cells may accumulate more random changes or mutations. This is because sperm cells continuously divide and replicate throughout a man’s life. Over time, errors can occur in the DNA that is passed on to the child.

The older the father, the more chances there are for these errors to accumulate. While most of these mutations are harmless, some may lead to de novo mutations in the child’s DNA, potentially causing genetic disorders or other health conditions.

In summary, as fathers age, the risk of de novo mutations in their offspring increases due to the accumulation of genetic changes in their sperm cells over time.

It’s important to note that while the risk of de novo mutations increases with paternal age, the overall risk remains relatively low. Advanced paternal age is just one of several factors that can contribute to de novo mutations, and most children born to older fathers are healthy. However, the increased risk underscores the importance of prenatal testing (like SMART TEST) in older couples who plan to have children.

At London Pregnancy Clinic, we offer a range of NIPT options including UNITY and PrenatalSafe. However, there are other brands of NIPT available that also provide screening for single gene disorders and other specific genetic conditions.

KNOVA NIPT, developed by Fulgent Genetics, is a brand of NIPT that includes screening for single gene disorders alongside common chromosomal anomalies. This comprehensive approach allows for a broader spectrum of prenatal screening, encompassing a variety of genetic conditions beyond the typical scope of most NIPTs.