Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions

Topic: Brain proteins, microglia and lab models

Down syndrome (DS), caused by trisomy of chromosome 21, exhibits significant phenotypic variability, including intellectual disability, early-onset Alzheimer disease (AD), congenital heart defects (CHDs), haematological malignancies, and immune dysregulation. While gene dosage effects have long been recognized, emerging evidence suggests that additional genetic variants contribute to individual differences in disease susceptibility and clinical outcomes. In this context, we reviewed genetic variants associated with DS phenotypes, aiming to elucidate genotype–phenotype correlations and explore their potential clinical applications in precision medicine. To achieve this, we analyzed literature published between 2000 and 2024 from databases such as PubMed, Scopus, and Web of Science, focusing on studies utilizing next-generation sequencing (NGS), whole exome sequencing (WES), genome-wide association studies (GWAS), and transcriptomic profiling to identify critical genetic alterations and gene networks associated with DS-related conditions. Our review highlights that variants in APP and BACE2 influence Aβ metabolism and contribute to AD risk in DS, while APOE and PICALM variants are implicated in neurodegeneration. CHDs are associated with variants in CRELD1, COL6A1/2, and other genes involved in extracellular matrix (ECM) organization. Additionally, blood disorders such as myeloid leukaemia in Down syndrome (ML-DS) are linked to mutations in GATA1 and aberrant signalling involving JAK2 and CRLF2. Immune dysregulation in DS appears to be influenced by alterations in IFNAR1/2 and polymorphisms in TRPM2 and OAS1. Collectively, these findings underscore the potential for targeted therapies, including BACE inhibitors, JAK-STAT pathway modulators, and immunomodulatory agents. Ultimately, understanding DS’s complex genetic architecture through integrated multi-omics and clinical profiling holds promise for the development of personalized interventions and the advancement of genotype-informed precision medicine.

@article{moka2025-a67d150e,
  author  = {Moka, Rajasekhar and Sudheer, Manjima and Kumar, Prabodh},
  title   = {{Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions}},
  journal = {International Journal of Genetics and Genomics},
  year    = {2025},
  doi     = {10.11648/j.ijgg.20251302.14},
  url     = {https://doi.org/10.11648/j.ijgg.20251302.14}
}

Key findings

• Down syndrome (DS), caused by trisomy of chromosome 21, exhibits significant phenotypic variability, including intellectual disability, early-onset Alzheimer disease (AD), congenital heart defects (CHDs), haematological malignancies, and immune dysregulation.
• While gene dosage effects have long been recognized, emerging evidence suggests that additional genetic variants contribute to individual differences in disease susceptibility and clinical outcomes.
• In this context, we reviewed genetic variants associated with DS phenotypes, aiming to elucidate genotype–phenotype correlations and explore their potential clinical applications in precision medicine.
• To achieve this, we analyzed literature published between 2000 and 2024 from databases such as PubMed, Scopus, and Web of Science, focusing on studies utilizing next-generation sequencing (NGS), whole exome sequencing (WES), genome-wide association studies (GWAS), and transcriptomic profiling to identify critical genetic alterations and gene networks associated with DS-related conditions.
• CHDs are associated with variants in CRELD1, COL6A1/2, and other genes involved in extracellular matrix (ECM) organization.

Why it matters

This review describes genetic variants, including in APP, BACE2, APOE, and PICALM, that contribute to Alzheimer's disease risk in people with Down syndrome. It highlights the complexity of genotype-phenotype relationships and the potential for precision medicine, but does not report a treatment or cure.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.11648/j.ijgg.20251302.14
• Original source →
• Free full text: International Journal of Genetics and Genomics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

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Studies this one cites

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• The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies Proceedings of the National Academy of Sciences of the United States of America · 2009-07-13 · usefulness score 57/100 · Down syndrome and Alzheimer's
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Studies sharing this one's topic tags

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• Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study The Lancet. Neurology · 2024-05-01 · usefulness score 67/100 · shares: down, syndrome

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