Uncovering the Genetics Underlying Rare Diseases

Genetics provides an understanding of the biological foundations that explain the structure and function of living organisms, as well as how this information is passed from one generation to the next through inheritance. In humans, we typically observe this inheritance through the traits that parents and children share.

The processes of information transfer and inheritance have a biochemical basis in the DNA molecule. These processes are characterized by their biological complexity, which involves the functioning of cells in the various tissues and organs that constitute the human body, as well as the hereditary transmission between individuals across generations. DNA contains the genetic information that is organized into genes, each of which can have defined and often multiple functions. When a sperm fertilizes an egg to form a zygote, this genetic information is already present. How is this DNA expressed to develop an embryo and later a fetus during prenatal development, and eventually grow and develop into a mature individual who ages over time?

This complex process is regulated by various molecules, allowing genes to be expressed in various tissues and at specific times. The genes are transcribed into RNA, which is then translated into proteins. Both RNA and proteins perform vital metabolic and physiological functions within cells and also facilitate communication between them. Additionally, hormones synthesized in the body enable communication between different organs.

Gene expression is a process that is highly regulated by transcription factors and epigenetic mechanisms, allowing for a precise adaptation to the requirements of homeostasis (internal milieu) and the surrounding physical, chemical and nutritional environment.

The intersection between genetics and rare diseases is essential for medical and scientific understanding of these disorders, which in turn influences the healthcare services provided. This connection is crucial for addressing key clinical aspects such as diagnosis, treatment, prevention and genetic counseling of the disease.

Rare Disease International defines a rare disease (RD) as a medical condition with a specific pattern of clinical signs, symptoms and findings that affects fewer than or equal to 1 in 2000 persons living in any WHO-defined region of the world. Many rare diseases are genetic disorders, but can also include rare cancers, rare infectious diseases, rare poisonings, rare immune-related diseases, rare idiopathic diseases and rare undetermined conditions.

RDs are a global healthcare priority and challenge for health professionals, scientific researchers, affected people, and their families. As a whole, they represent a broad group of disorders with highly diverse clinical, pathophysiological and prognostic features. (Orphanet recognizes 6,528 RDs, reviewed August 17, 2025; OMIM includes 7,645 clinical phenotypes for which the molecular basis is known, updated August 15, 2025). A large proportion of RDs (50-70%) have onset in childhood and result in high rates of mortality and morbidity, and represent the most significant cause of death in children in high-income countries.

A substantial proportion of rare diseases, estimated to be between 70 and 80 percent, are classified as genetic disorders. These disorders arise from the presence of one (dominant) or two (recessive) genetic variants, known as pathogenic variants, which are responsible for the individual developing the disease. When an individual carries a dominant variant or two recessive variants, it leads to the development of the disease due to changes in homeostasis that affect the individual's physiology. These variants are highly penetrant, meaning they consistently lead to pathophysiological alterations that produce variable clinical manifestations, symptoms, and signs of the disease. Understanding this underlying pathogenic genetic variation is crucial, as it explains the cause of the disease and plays a crucial role in the medical management of people living with a rare disease (PLWRD).

The genetic variant serves as a fundamental biomarker for disease management, while the gene becomes the molecular target for treatment and therapeutic research focused on the underlying pathophysiological process of the disease. What does this mean, and how does it apply to the entire continuum of illness and medical care for PLWRD?

Here are some key elements to consider:

(a) When diagnosing a patient whose clinical presentation and history suggest a rare disease, especially if a genetic basis is suspected, it is crucial to identify the pathogenic genetic variant(s) that cause the disease. This identification provides a definitive etiological diagnosis. Genomic analysis, supported when necessary by multi-omics approaches, can facilitate this process.

Next-generation DNA sequencing (DNA-seq), whether short or long reads, of the exome or genome, combined with RNA-seq and methylation profiles related to neurodevelopmental genetic syndromes (DNAm), enables diagnostic rates of approximately 50 percent of patients. As new biological insights and multi-omics knowledge continue to grow, this rate is expected to increase.

(b) Genes and the biological and biochemical pathways they participate in are therapeutic targets. This allows for the development of new genetic or pharmacological treatments aimed at specific targets. Notable examples include antisense oligonucleotide therapy and gene therapy for spinal muscular atrophy and drug repurposing strategies for Menkes disease.

(c) In reproductive medicine, studying genetic variants enables secondary prevention of having children affected by serious rare diseases. For couples with a family history of a rare monogenic or Mendelian disease, particularly those that manifest in childhood, pre-implantation genetic diagnosis or prenatal diagnosis of the pathogenic variant can be offered. The last can be done using fetal DNA obtained through chorionic villus sampling or amniocentesis. Currently, the analysis of circulating fetal DNA in maternal blood is primarily applied to identify chromosomal and genomic syndromes.

Additionally, there has been a rise in studies utilizing genomic analysis in newborn screenings, complementing traditional biochemical methods. This is particularly beneficial for rare diseases that lack biochemical, endocrinological, hematological or immunological markers, as genomic variant analysis may be the only available biomarker for many conditions. For recessive diseases, whether autosomal or X-linked, systematic screening of carriers in the general population can facilitate primary prevention.

(d) Finally, the availability of the genetic variant(s) in a patient and his/her family, along with family history, allows for more accurate and targeted genetic counseling. This genetic counseling helps people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. It includes assessing the chance of disease occurrence or recurrence, education about inheritance, testing, management, prevention, resources and research and counseling to promote informed choices and adaptation to the risk or condition.

We are exploring how understanding the mechanisms by which individuals develop illnesses can be leveraged to support people living with a rare disease. This offers hope for patients and their families, and has the potential to significantly improve their lives.