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

Raja Sekhar Moka; Meenakshi Puliyath Sudheer; Prabodh Kumar

doi:doi:10.11648/j.ijgg.20251302.14

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

Raja Sekhar Moka^*, Meenakshi Puliyath Sudheer, Prabodh Kumar

Published in International Journal of Genetics and Genomics (Volume 13, Issue 2)

Received: 16 April 2025 Accepted: 27 April 2025 Published: 3 June 2025

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Abstract

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.

Published in	International Journal of Genetics and Genomics (Volume 13, Issue 2)
DOI	10.11648/j.ijgg.20251302.14
Page(s)	42-50
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2025. Published by Science Publishing Group

Keywords

Down Syndrome (DS), Trisomy 21, Phenotypic Variability, Intellectual Disability, Early-onset Alzheimer’s Disease (AD), Congenital Heart Defects (CHDs), Hematological Malignancies

References

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Moka, R. S., Sudheer, M. P., Kumar, P. (2025). Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. International Journal of Genetics and Genomics, 13(2), 42-50. https://doi.org/10.11648/j.ijgg.20251302.14

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Moka, R. S.; Sudheer, M. P.; Kumar, P. Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. Int. J. Genet. Genomics 2025, 13(2), 42-50. doi: 10.11648/j.ijgg.20251302.14

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Moka RS, Sudheer MP, Kumar P. Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. Int J Genet Genomics. 2025;13(2):42-50. doi: 10.11648/j.ijgg.20251302.14

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@article{10.11648/j.ijgg.20251302.14,
  author = {Raja Sekhar Moka and Meenakshi Puliyath Sudheer and Prabodh Kumar},
  title = {Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions
},
  journal = {International Journal of Genetics and Genomics},
  volume = {13},
  number = {2},
  pages = {42-50},
  doi = {10.11648/j.ijgg.20251302.14},
  url = {https://doi.org/10.11648/j.ijgg.20251302.14},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijgg.20251302.14},
  abstract = {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.
},
 year = {2025}
}

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TY  - JOUR
T1  - Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions

AU  - Raja Sekhar Moka
AU  - Meenakshi Puliyath Sudheer
AU  - Prabodh Kumar
Y1  - 2025/06/03
PY  - 2025
N1  - https://doi.org/10.11648/j.ijgg.20251302.14
DO  - 10.11648/j.ijgg.20251302.14
T2  - International Journal of Genetics and Genomics
JF  - International Journal of Genetics and Genomics
JO  - International Journal of Genetics and Genomics
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PB  - Science Publishing Group
SN  - 2376-7359
UR  - https://doi.org/10.11648/j.ijgg.20251302.14
AB  - 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.

VL  - 13
IS  - 2
ER  -

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Raja Sekhar Moka

Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India

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Meenakshi Puliyath Sudheer

Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India

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Prabodh Kumar

Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India

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Moka, R. S., Sudheer, M. P., Kumar, P. (2025). Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. International Journal of Genetics and Genomics, 13(2), 42-50. https://doi.org/10.11648/j.ijgg.20251302.14

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ACS Style

Moka, R. S.; Sudheer, M. P.; Kumar, P. Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. Int. J. Genet. Genomics 2025, 13(2), 42-50. doi: 10.11648/j.ijgg.20251302.14

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AMA Style

Moka RS, Sudheer MP, Kumar P. Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions. Int J Genet Genomics. 2025;13(2):42-50. doi: 10.11648/j.ijgg.20251302.14

Copy | Download

@article{10.11648/j.ijgg.20251302.14,
  author = {Raja Sekhar Moka and Meenakshi Puliyath Sudheer and Prabodh Kumar},
  title = {Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions
},
  journal = {International Journal of Genetics and Genomics},
  volume = {13},
  number = {2},
  pages = {42-50},
  doi = {10.11648/j.ijgg.20251302.14},
  url = {https://doi.org/10.11648/j.ijgg.20251302.14},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijgg.20251302.14},
  abstract = {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.
},
 year = {2025}
}

Copy | Download

TY  - JOUR
T1  - Unraveling the Genetic and Phenotypic Complexity of Down Syndrome from Trisomy 21 to Comorbid Conditions

AU  - Raja Sekhar Moka
AU  - Meenakshi Puliyath Sudheer
AU  - Prabodh Kumar
Y1  - 2025/06/03
PY  - 2025
N1  - https://doi.org/10.11648/j.ijgg.20251302.14
DO  - 10.11648/j.ijgg.20251302.14
T2  - International Journal of Genetics and Genomics
JF  - International Journal of Genetics and Genomics
JO  - International Journal of Genetics and Genomics
SP  - 42
EP  - 50
PB  - Science Publishing Group
SN  - 2376-7359
UR  - https://doi.org/10.11648/j.ijgg.20251302.14
AB  - 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.

VL  - 13
IS  - 2
ER  -

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