Can we look earlier?
Your baby appears healthy.
The pregnancy has been uneventful, or perhaps accompanied only by minor concerns. Routine newborn screening — the familiar heel-prick test — has been performed, or will be performed, and there is no specific reason to suspect a genetic disorder.
But some genetic diseases are present before their symptoms are.
Summarizing, more parents are starting to ask a very simple question: “We just had a healthy baby: can we screen them for genetic diseases or syndromes that may appear during childhood?”
Some become apparent during the first months of life. Others emerge during childhood or adolescence.
Whole exome sequencing makes it possible to investigate thousands of genes simultaneously, even when there is no specific disease to search for.
More parents are beginning to ask whether they can screen their healthy newborn for genetic disorders that may emerge during childhood. They are not necessarily looking for a broad prediction of everything that might happen over a lifetime. They want to know whether a genetic condition relevant to their child’s health may already be present — and whether finding it earlier could make a difference.
From diagnosing later to finding it earlier.
→ If this situation sounds familiar, the diagnostic pathway can start here.
Can a healthy newborn have a genetic disease?
The answer is very simple: yes.
Some pediatric genetic disorders manifest themselves at birth or during the first days of life. But many others have their onset during the first months or years of life. Most strikingly, some may emerge after an apparently normal period of growth and development, sometimes leading to developmental arrest or regression, with important consequences for the child and the entire family.
Other genetic disorders become apparent only during later childhood or adolescence, leaving an even longer period apparently free of disease. Although these conditions may interfere less with early development than disorders arising during the first years of life, their clinical consequences can be equally severe.
Finally, there are borderline situations. Some pathogenic genetic variants are predominantly associated with disorders of adult onset and would therefore not normally be actively screened for in an infant. However, the boundary is not always absolute: some conditions may exceptionally manifest before adulthood, while others may become clinically relevant in early adulthood, when a young person may still be closely supported by their family.
This creates an important question in broad genomic screening: where should pediatric screening end, and future adult health begin?
Genetic disease may be present before symptoms appear
A pathogenic variant can be present from birth,
while clinical manifestations
may emerge months or years later.
Genetic diseases that may appear during infancy or childhood
Genetic diseases and syndromes that may arise during the perinatal period — the first days or weeks after birth —, during infancy and childhood, or later in adolescence can differ widely in severity, clinical expression within the same family and, of course, penetrance. These are specific genetic concepts, but they become particularly important when considering pediatric disorders that have not yet manifested.
Severity can vary enormously: from metabolic conditions that can be effectively managed with dietary interventions or specific treatments, to severe developmental regression, isolated hearing or vision loss of different degrees, and many other clinical presentations.
Intrafamilial clinical variability explains some cases in which a child suddenly or progressively develops a disorder that is also present in one of the parents, but to a much lesser and less recognizable extent. This may occur, for instance, in some neurodevelopmental disorders: a parent may have experienced only learning or speech difficulties during childhood, while their child presents with similar difficulties accompanied by a much more significant cognitive impairment.
The genetic condition may be the same. Its clinical expression may not be.
Incomplete penetrance describes a related but different situation: a disease-causing genetic variant may be present in a completely asymptomatic parent and nevertheless be transmitted to a child who develops the associated disorder.
Clinical variability and incomplete penetrance are particularly relevant in many autosomal dominant disorders, in which a pathogenic variant can be transmitted from an affected or apparently unaffected parent to their child. In such cases, each pregnancy may carry a 50% probability of transmitting the variant.
This also illustrates why broader genomic screening may provide information that a restricted newborn gene panel cannot. Whole exome or whole genome sequencing can investigate a much broader spectrum of genes associated with pediatric-onset disorders rather than limiting the analysis to a predefined selection.
Identifying a clinically relevant variant in a newborn can sometimes provide information not only for that child, but also for the parents and for future pregnancies.
Choosing this type of screening may therefore reflect a particularly forward-looking approach to a child’s health. Some parents may initially wonder whether looking this deeply in an apparently healthy newborn means looking for too much, too early. When the analysis is deliberately focused on conditions relevant to pediatric health, however, the choice can reflect a simple principle: if clinically meaningful information can be found before disease appears, knowing earlier may create opportunities that knowing later cannot.
At the same time, looking earlier does not necessarily mean looking for everything. The purpose of pediatric genomic screening is not to predict every possible genetic condition that could affect a person throughout their lifetime, but to define a clinically appropriate scope of analysis for the child.
This is also why, at Breda Genetics, we consider post-natal genomic screening a specific application of the same exome or genome sequencing used in diagnostic pediatric genetics, rather than a purely predictive or proactive application of genomic testing. The technology may be the same; what changes is when we look, what we look for, and what we consider clinically relevant for the child.
Overall, virtually every organ and system can be affected by genetic disorders with pediatric onset:
- Metabolic and mitochondrial disorders
- Neurological and neurodevelopmental disorders
- Epileptic disorders
- Neuromuscular diseases
- Inherited cardiac diseases and arrhythmias
- Primary immunodeficiencies
- Kidney and urinary disorders
- Inherited hearing loss and eye diseases
- Endocrine disorders
- Hematological disorders
- Connective tissue and skeletal disorders
Same technology. Different timing. Different clinical purposes.
Exome and genome sequencing may use the same genomic technologies, but their clinical meaning changes according to when and why they are performed.
(EXOME PLUS) Symptoms are already present
Genomic testing is used to investigate an existing clinical condition and search for its molecular cause.
(EXOME PLUS POST-NATAL) The child appears healthy
Pediatric-onset genetic conditions are investigated earlier, before their clinical manifestations become evident.
(EXOME/GENOME PRO) Future health is explored more broadly
The analysis considers genetic risks that may become relevant across a much wider portion of the individual's lifetime.
Why are some genetic diseases not visible at birth?
A genetic disease does not necessarily begin when its first symptoms appear.
Genetic variants responsible for disease are already present at birth and may affect protein function and the associated cellular or metabolic processes long before their clinical consequences become visible.
This interval between the presence of the genetic cause and the appearance of symptoms is part of the natural history of the disease.
There are several reasons why this may happen.
Some genetic disorders become apparent only when a particular organ or biological system reaches a certain stage of development. In some neurological and neuromuscular diseases, for example, early development may appear normal before developmental delay, progressive weakness, loss of previously acquired abilities or regression becomes evident.
Other disorders result from the progressive accumulation of cellular, biochemical or metabolic dysfunction. For a period of time, the body may compensate effectively. Symptoms emerge only when this compensation is no longer sufficient and a clinical threshold is reached.
In some conditions, the first manifestation may instead be triggered by a physiological challenge. A child with an underlying metabolic disorder may appear completely healthy until fasting, fever, infection or another period of increased metabolic demand reveals a previously silent biochemical vulnerability.
The same principle applies to other organ systems. Some inherited cardiac disorders may remain clinically silent until an arrhythmia or another cardiac manifestation occurs. Some genetic forms of hearing or vision impairment may become evident only when sensory function begins to deteriorate. Certain immune disorders may become recognizable only after recurrent or unusually severe infections start to occur.
This creates a fundamental limitation when assessing a newborn exclusively on the basis of their current phenotype:
absence of symptoms at birth does not necessarily mean absence of genetic disease.
In fact, conventional newborn screening was developed precisely around this principle: identifying selected disorders before symptoms appear, when early treatment or surveillance may substantially change the child’s outcome.
However, while conventional newborn screening is intentionally targeted to a limited group of conditions, customized post-natal whole exome sequencing (our EXOME PLUS POST-NATAL) can investigate, also taking family history into account, a much broader spectrum of genetic diseases that may manifest during infancy, childhood or adolescence.
What does routine newborn screening detect?
Routine newborn screening is one of the most successful examples of preventive medicine: it looks for disease before a newborn develops symptoms, precisely because identifying certain conditions early can substantially change their clinical course.
In Italy, as in many other countries, newborns undergo a heel-prick blood test during the first days of life. The Italian Screening Neonatale Esteso (SNE) currently investigates approximately 40 inherited metabolic diseases, while the national newborn screening framework also includes early screening for congenital hearing loss and congenital cataract. The screening programme has progressively expanded, and Italian legislation has also provided for its extension to genetic neuromuscular diseases, severe congenital immunodeficiencies and lysosomal storage disorders.
The principle behind newborn screening is extremely powerful: do not wait for symptoms when detecting a disease earlier can make a difference.
However, routine newborn screening was never designed to investigate every genetic disease that may affect a child.
Its strength comes precisely from being highly targeted. Conditions are selected according to specific screening criteria, including their natural history, the availability of a reliable screening method and, importantly, the possibility that early diagnosis and intervention may improve the child’s outcome.
This also means that a normal newborn screening result does not indicate that a child is free from genetic disease. It means that the newborn has not screened positive for the specific conditions included in that screening programme.
Thousands of genes are associated with disorders that can manifest during infancy, childhood or adolescence, involving the nervous system, muscles, heart, immune system, kidneys, hearing, vision and many other organs and biological processes. Most of these conditions are outside the scope of routine newborn screening.
Post-natal whole exome sequencing asks a broader question.
Rather than testing only for a predefined group of disorders included in a population screening programme, it allows thousands of genes to be examined simultaneously and the analysis to be clinically tailored to the newborn, their family history and the type of pediatric-onset conditions considered appropriate to investigate.
The two approaches should therefore not be considered alternatives.
Routine newborn screening identifies selected conditions for which population-wide early detection has demonstrated clinical value. Post-natal genomic screening can extend the investigation beyond those predefined conditions.
Can genetic testing go beyond routine newborn screening?
Yes. Today, genomic testing makes it possible to investigate a much broader spectrum of genetic conditions than those included in routine newborn screening.
Whole exome sequencing (WES) analyzes the protein-coding regions of thousands of genes simultaneously. Whole genome sequencing (WGS) extends the analysis beyond the exome, potentially identifying additional types of genetic variation across the genome.
For an apparently healthy newborn, however, the possibility of looking more broadly does not mean that every detectable genetic finding should necessarily be searched for or reported.
The fundamental question is not simply how much genetic information can be generated, but which information is clinically appropriate and potentially useful for that child.
This is why post-natal genomic screening should be clinically customized. The analysis can focus primarily on genetic conditions with pediatric onset, while also taking into account the newborn’s family history, pregnancy history and any relevant clinical information. The scope of the analysis and the management of findings that predict conditions predominantly arising in adulthood should be discussed before testing.
A broader genomic approach may also identify a genetic condition before the first clinical manifestations appear, potentially allowing earlier surveillance, specialist evaluation, preventive measures or treatment when these are available. In other cases, an early molecular diagnosis may simply provide the family and the child’s physicians with information that could become important if symptoms emerge later.
At Breda Genetics, this is the rationale behind EXOME PLUS POST-NATAL: a specific application of our clinical whole exome sequencing for apparently healthy newborns, designed to investigate a broad spectrum of genetic conditions relevant to pediatric health.
EXOME PLUS POST-NATAL is not intended to replace routine newborn screening, and it is not designed to predict everything that might happen throughout a person’s lifetime.
It is a way of looking further — while keeping the child’s present and future clinical interests at the center of the analysis.
EXOME PLUS POST-NATAL: a deeper newborn screening.
From diagnosing later to finding it earlier.
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