For decades, Down syndrome was a medical mystery. Now, science is rewriting the story one gene at a time.
Babies born with Down syndrome
Chromosome with extra copy
Individuals in Trisome Project
In every cell of the human body, our genetic blueprint is neatly packaged into 46 chromosomes—except when it's not. For the approximately 1 in 700 babies born with Down syndrome, that blueprint contains an extra copy of chromosome 21, a genetic condition known as trisomy 21 6 . This additional genetic material, while small (chromosome 21 is the smallest human chromosome), sets in motion a cascade of biological effects that manifest as the characteristic features of Down syndrome.
Functional genomics represents a revolutionary approach to understanding this condition. Rather than simply cataloging genes, it investigates how they operate and interact—asking not just "which genes are present?" but "what are they doing?" 3 4 . Through this powerful lens, scientists are discovering that trisomy 21 changes human biology in unique ways as individuals grow and age, with some effects consistent throughout life and others specific to certain developmental stages 1 . These insights are paving the way for unprecedented opportunities to improve health and quality of life for people with Down syndrome across their lifespans.
Functional genomics moves beyond static genetic maps to explore the dynamic functions of genes and their products. It investigates how genes are expressed, how proteins interact, and how metabolic pathways function—essentially, how the instructions in our DNA are carried out within our cells 3 4 . For Down syndrome research, this means studying how that extra chromosome 21 disrupts normal biological processes, leading to the various health and developmental characteristics associated with the condition.
Early research attempted to pinpoint a specific "critical region" on chromosome 21 responsible for most Down syndrome features. However, functional genomics has revealed a more complex picture. Scientists now understand that no single gene or region causes all characteristics of Down syndrome 6 . Instead, multiple critical regions or critical genes interact to produce the varied phenotypic traits 6 . The dosage imbalance created by the extra chromosome affects not just chromosome 21 genes themselves, but has ripple effects across the entire genome, altering the expression and regulation of many other genes 6 .
Key Insight: The effects of trisomy 21 extend far beyond chromosome 21 itself, creating a network of genetic disruptions that collectively produce the characteristics of Down syndrome.
Groundbreaking research from the Crnic Institute's Human Trisome Project has revealed that the biological impacts of trisomy 21 are not static but evolve significantly throughout life 1 2 . Their study of over 300 individuals with Down syndrome uncovered striking age-specific effects:
Some biological processes remain dysregulated across all ages, including immune hyperactivity and disrupted oxygen metabolism 1 .
The majority of biological changes occur only during specific developmental periods. When examining genes, proteins, metabolites, and immune cell types affected by trisomy 21 in children versus adults, the changes unique to one age group consistently outnumber those conserved across the lifespan 1 2 .
The researchers identified eight major temporal trajectories for gene expression, protein levels, metabolite levels, and immune cell frequencies in the bloodstream, demonstrating that biological aging in Down syndrome is not a linear process 1 2 . These findings underscore the need for age-specific approaches to both research and clinical care.
| Trajectory Type | Biological Components Measured | Age Range Studied |
|---|---|---|
| Gene Expression | How genes are turned on/off | 6 months to 60+ years |
| Protein Levels | Presence and quantity of proteins | 6 months to 60+ years |
| Metabolite Levels | Small molecule products of metabolism | 6 months to 60+ years |
| Immune Cell Frequencies | Types and numbers of immune cells | 6 months to 60+ years |
Rapid developmental changes, immune system maturation, and neurological development are most prominent during this period.
Hormonal changes, continued brain development, and emergence of specific health concerns related to trisomy 21.
Stabilization of some systems, but increased risk for certain conditions like early-onset Alzheimer's disease.
Accelerated aging processes, increased prevalence of age-related conditions, and unique geriatric concerns.
One of the most revolutionary experiments in functional genomics of Down syndrome comes from recent work by Ryotaro Hashizume and colleagues, who demonstrated that CRISPR-Cas9 gene editing could potentially correct trisomy 21 at the cellular level 7 .
The researchers designed specialized CRISPR guides to target only the extra chromosome 21, using a process called allele-specific editing that directs the cutting enzyme to the desired spot .
The technique was tested on previously generated trisomy 21 cell lines derived from both pluripotent cells and skin fibroblasts 7 .
The CRISPR-Cas9 system was used to cleave the third chromosome in these cell lines. The system was designed to identify which chromosome had been duplicated to ensure the cell didn't end up with two identical copies after removal, but instead had one from each parent 7 .
The researchers found that suppressing chromosomal DNA repair ability increased the rate of duplicate chromosome elimination 7 .
The experiment yielded several significant results:
| Parameter Measured | Before Chromosome Removal | After Chromosome Removal |
|---|---|---|
| Gene Expression Patterns | Abnormal | Normalized |
| Nervous System Development Genes | Less active | More active |
| Metabolism-related Genes | Overactive | Less active |
| Cell Growth Rate | Slower | Faster |
| Cell Doubling Time | Longer | Shorter |
Research Note: While this approach is not yet ready for clinical application—partly because the current technique can also affect the retained chromosomes—it represents a groundbreaking proof of concept that could eventually form the basis of novel medical interventions for people with Down syndrome 7 .
Functional genomics research relies on sophisticated tools and technologies. Here are some key components of the modern Down syndrome research toolkit:
| Research Tool | Function in Down Syndrome Research |
|---|---|
| CRISPR-Cas9 Gene Editing | Targets and removes extra chromosomes or modifies specific genes 7 |
| Induced Pluripotent Stem Cells (iPSCs) | Creates patient-specific cell models for studying disease mechanisms 7 |
| Multi-omics Technologies | Simultaneously analyzes genes, proteins, metabolites for comprehensive profiling 1 |
| Animal Models (Ts66Yah mice) | Provides enhanced models that more precisely capture Down syndrome genetics for preclinical studies 8 |
| Biobanks | Stores biological samples for large-scale studies across research institutions 1 |
Precision gene editing technology that allows targeted modification of genetic sequences, including potential correction of trisomy 21.
Induced pluripotent stem cells created from patient samples, enabling personalized disease modeling and drug testing.
Integrated analysis of genomics, transcriptomics, proteomics, and metabolomics for comprehensive biological profiling.
The insights from functional genomics are already shaping the future of Down syndrome research and care. The NIH's INCLUDE Project, launched in 2018, represents a comprehensive effort to understand co-occurring conditions across the lifespan 5 9 . This initiative has three main components:
Conducting targeted basic science studies on chromosome 21 and Down syndrome
Assembling a large cohort of individuals with Down syndrome across the lifespan
Including individuals with Down syndrome in existing and future clinical trials 9
Research priorities include investigating impaired musculoskeletal growth, accelerated immune aging, and the development of precision medicine approaches that consider an individual's unique genetic, environmental, and lifestyle factors to promote brain health across the lifespan 1 5 .
Functional genomics has transformed our understanding of Down syndrome from a static genetic condition to a dynamic interplay of biological processes that evolve across the lifespan. The groundbreaking discoveries emerging from laboratories worldwide—from the age-specific biological changes mapped by the Human Trisome Project to the revolutionary potential of chromosome editing—herald a new era where interventions may be precisely tailored to an individual's age and specific genetic profile.
As Dr. JoaquÃn Espinosa of the Crnic Institute notes, "These results reveal for the first time that trisomy 21 changes human biology in unique ways as persons with Down syndrome grow and age" 1 . This deeper understanding promises not only to extend life expectancy but to significantly enhance quality of life for millions of people with Down syndrome worldwide.
The future of Down syndrome research lies in embracing this complexity—recognizing that while trisomy 21 may be the genetic compass that sets the direction, the journey of discovery is only just beginning.