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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis

  • Sherin Ramadan1
  • Emanuele Panza2,3
  • Antonio Orlacchio1,4
4 affiliations
  1. 1Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
  2. 2Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
  3. 3Medical Genetics Unit, IRCCS Bologna University Hospital, 40138 Bologna, Italy
  4. 4Perugia University Hospital, 06132 Perugia, Italy
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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.

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Cite

BibTeXRIS
BibTeX
@article{ramadan2026beyond,
  title = {{Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis}},
  author = {Sherin Ramadan and Emanuele Panza and Antonio Orlacchio},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27209350},
  url = {https://www.mdpi.com/1422-0067/27/20/9350},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis
AU  - Sherin Ramadan
AU  - Emanuele Panza
AU  - Antonio Orlacchio
PY  - 2026
DA  - 2026/10/01
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27209350
UR  - https://www.mdpi.com/1422-0067/27/20/9350
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.
SN  - 1422-0067
ER  -