Genetic Testing and Its Role in Diagnosing Hereditary Disorders

1. What is DNA and How Does It Affect Health

Deoxyribonucleic acid (DNA) is a molecule that contains a cell’s genetic information. DNA is inherited from parents and encodes thousands of genes that provide instructions for growth, development, and bodily functions. Each gene contains information for producing a protein or regulating other genes’ activity. Changes in DNA, known as mutations or variants, can affect protein function and lead to various diseases. However, most people have many gene variants, the majority of which are harmless and do not impact health. Only specific DNA changes can cause genetic disorders.

2. What is Genetic Testing: Goals, Types, and Applications

Genetic testing involves analyzing DNA, typically from blood or saliva samples, to identify changes (mutations or variants) in genes. Its goals may include confirming a diagnosis of a hereditary disease, assessing risk, determining predisposition to diseases, or guiding therapy. For example, genetic tests can detect Fragile X syndrome or evaluate the risk of developing cancers. Various types of tests exist:

• Targeted testing (single-gene sequencing): Used when a specific disease caused by a single gene is suspected (e.g., mutations in the DMD gene for Duchenne muscular dystrophy or the HBB gene for sickle cell anemia). This method is highly accurate but covers only one gene.
• Gene panel testing: Simultaneous testing of multiple, dozens, or even hundreds of genes associated with a specific group of diseases. For instance, neurological or oncological symptoms may prompt panel testing for genes linked to developmental disorders, epilepsy, immunodeficiencies, or hereditary cancers.
• Whole-exome sequencing (WES): Analysis of all protein-coding regions of DNA (~2% of the genome). Most known pathogenic variants (~95%) are found in these regions. WES is widely used for diagnosing rare, unidentified diseases when other tests fail, enabling the detection of changes in thousands of genes simultaneously.
• Whole-genome sequencing (WGS): Analysis of the entire genome (both coding and non-coding regions). It provides a broader overview and can identify changes in regulatory regions. WGS covers up to 99% of genetic material and is becoming increasingly accessible.
• Chromosomal microarray analysis (CMA): Detects submicroscopic DNA deletions and duplications (copy-number variants, CNVs) across the genome. CMA is particularly useful for diagnosing patients with intellectual disability, developmental delays, or multiple congenital anomalies, as it detects even single missing or duplicated exons.
• Optical Genome Mapping (OGM): A new method for identifying small structural genomic changes (insertions, deletions, or rearrangements) that cannot be detected by standard sequencing methods.

3. Why Conduct Genetic Testing: Rationale and Indications

Genetic testing is ordered when a hereditary disease is suspected. Examples include symptoms appearing in childhood or with unusual characteristics (anatomical defects, developmental disorders, rare symptoms). Approximately 80% of rare diseases have a genetic origin (mostly monogenic), so timely genetic diagnosis helps establish an accurate diagnosis. Identifying a genetic cause provides doctors with critical information for selecting optimal treatment and monitoring plans, while enabling patients and families to make informed decisions about family planning and risk reduction. Genetic testing is also valuable for prevention: for instance, detecting BRCA1/2 mutations can lead to earlier monitoring and preventive measures to reduce the risk of breast or ovarian cancer. Testing is generally recommended when diagnosis based on symptoms, risk assessment for relatives, or an individualized approach to prevention and treatment is needed.

Indications for testing:

• If a child exhibits developmental delays, intellectual disability, congenital anomalies, or an unusual clinical presentation, chromosomal analysis or CMA is often the first step.
• If a specific genetic disease is suspected (e.g., based on family history or characteristic symptoms), a doctor may directly sequence the relevant gene or gene panel.
• After negative results from routine tests (biochemical, neurological, etc.), complex cases often proceed to WES or WGS to avoid missing rare genetic syndromes.

4. Main Methods of Genetic Analysis

• Sanger sequencing: A classic method that reads DNA sequences with exceptional accuracy. Considered the “gold standard,” Sanger sequencing is particularly useful for analyzing single genes or confirming identified variants. It is well-suited for diagnosing diseases caused by mutations in a single, relatively short gene.
• MLPA (Multiplex Ligation-dependent Probe Amplification): A method for detecting DNA copy-number changes (CNVs) at the level of one or two exons. MLPA allows simultaneous checking for deletions or duplications in multiple gene regions. It is a fast and cost-effective method, often used for syndromes with frequent deletions (e.g., confirming Duchenne muscular dystrophy or exon “losses” in the BRCA gene).
• NGS panels: Sequencing of large gene sets (tens to hundreds) linked to specific clinical conditions. Using high-throughput next-generation sequencers (NGS), multiple genes can be tested simultaneously. Panels detect single nucleotide changes and some structural changes within exons but may miss non-coding regions and have limitations in CNV size detection. Panel development requires complex bioinformatics, but clinical labs widely use them for their efficiency and ability to test multiple variants at once.
• Whole-exome sequencing (WES): Analysis of the “exome” – all protein-coding regions of the genome. Most disease-causing mutations (~95%) are located in these regions. Exome-seq generates vast data and is often used for unidentified rare diseases. Its diagnostic yield depends on the condition (e.g., 30–50% for developmental disorders). WES may miss larger structural variants outside exons but can be supplemented with CNV analysis, mitochondrial genome analysis, or deeper interpretation.
• Whole-genome sequencing (WGS): Sequencing of the entire genome (coding and non-coding regions). The most comprehensive method, it detects nearly all genetic variants, including deep intronic mutations, regulatory elements, and most structural variants. WGS is more expensive than WES but is becoming more accessible as costs decrease. It is most justified when prior methods fail and a “targeted” genome reconstruction is needed.
• Chromosomal microarray analysis (CMA): Genome-wide scanning using microarrays (aCGH or SNP-array) to detect submicroscopic CNVs. CMA identifies deletions and duplications from hundreds of base pairs upward, surpassing the resolution of standard karyotyping. However, unlike WGS and OGM, it cannot detect balanced rearrangements (translocations, inversions) without DNA copy changes.
• Optical Genome Mapping (OGM): A novel method for identifying small structural genomic changes (insertions, deletions, or rearrangements) undetectable by standard sequencing methods.

Each method has its advantages and limitations, so the choice of analysis depends on the clinical situation.

5. How Doctors Choose the Optimal Diagnostic Pathway

Doctors select the testing sequence based on clinical signs, family history, and available resources. Sometimes a strategic “simple-to-complex” approach is used: starting with one or a few likely genes, then moving to broader tests if results are negative. In other cases, a “genomic-first” approach is applied, immediately using broad panels or WES/WGS, especially for complex, unknown cases. Increasingly, clinics adopt a “genotype-first” strategy: instead of multiple clarifying tests, exome/genome sequencing is performed upfront, significantly reducing time to diagnosis. Existing information, such as the hereditary nature, symptom severity, and uniqueness, helps doctors choose the optimal test (specialized panel or broad sequencing) for rapid and effective diagnosis.

6. What to Do If Results Are Inconclusive

• Variant of Uncertain Significance (VUS): Sometimes a test identifies a genetic change, but insufficient data exist about its role in disease. Such results are called VUS and are neither “positive” nor “negative” clinically, so they cannot guide treatment. In these cases, genetic counseling is recommended: additional family testing (segregation analysis), population frequency data, or functional studies may help reclassify the VUS. Most VUS are later found to be benign: for example, a large study reclassified 91% of reviewed VUS as “benign” and only 9% as “pathogenic.”
• Negative result: The absence of detected DNA changes does not rule out a genetic cause. Reasons may include inaccessible genomic regions, unknown genes, or inaccurate clinical interpretation. Reanalyzing existing data with updated algorithms or new gene function knowledge can yield diagnoses in 10–20% of previously unresolved cases. Alternative analyses (e.g., CMA if not previously done, or sequential exon sequencing) may be ordered. If these fail, patients may join research programs for “unexplained cases” to identify new genes.
• Next steps: Consult a geneticist and counselor to interpret results. If no answers are found, retain “raw” sequencing data if possible. Laboratories can periodically reanalyze them as new studies uncover associations. Patients are often asked to reconnect with the clinic after a few years for reinterpretation.

7. Advantages of a Multidisciplinary Approach

Multidisciplinary team: Modern genetic diagnostics requires collaboration among clinical geneticists, specialists (psychiatrists, neurologists, pediatricians, etc.), laboratory geneticists, and counselors. Reviews show that such teams significantly improve diagnostic efficiency and interpretation quality for complex cases, adding 6–25% new diagnoses in challenging cases. Teams resolve “uncertain” variants faster, accelerate diagnosis, and enable personalized treatment or monitoring strategies.

Genetic counseling: Before any testing, geneticists help patients understand the best test and potential outcomes. Post-test, they explain results and discuss next steps. As noted by the CDC, genetic counseling ensures “the right test is done for the right person” and helps “understand the results.” Thus, a multidisciplinary team, alongside geneticists and counselors, provides comprehensive support and maximizes testing benefits.

8. Prospects: Personalized Medicine, Genetic Counseling, and Prevention

The advent of large-scale genetic data is transforming medicine into a more personalized field. Personalized (precision) medicine uses a patient’s genetic information to optimize prevention, diagnosis, and treatment. For example, knowing a genotype can guide individualized therapy, predict disease risk, and develop tailored prevention strategies (monitoring, lifestyle changes, etc.).

Oncology counseling and prevention are advancing: genomics enables identifying at-risk groups before disease onset and offering screening programs. For instance, BRCA mutation screening helps detect patients at higher cancer risk, enabling timely preventive monitoring. The CDC notes that doctors may recommend genetic counseling and testing based on family history, suggesting broader future applications.

Emerging technologies, such as gene-targeted therapies (e.g., CRISPR and other genome-editing methods), expanded neonatal screening programs using sequencing (e.g., newborn exome analysis), and polygenic risk scoring are promising directions. Studies show that combined genetic testing with early intervention can prevent significant premature deaths. However, the growing volume of data complicates interpretation, making the role of qualified geneticists and multidisciplinary teams critical for accurate assessment and practical use of genetic data.

Every expert genetic test at our Center is accompanied by free counseling by a geneticist to explain the results.