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The SMN locus in the T2T era: Structure, gene conversion, and clinical implications
Demi Gommers1, Maria M Zwartkruis1, W Ludo van der Pol2
1Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
Trends in Genetics : TIG
|June 11, 2026
Summary
New sequencing technologies resolve complex genetic regions like the survival motor neuron (SMN) locus. This allows for a detailed understanding of genetic diversity, potentially improving spinal muscular atrophy diagnosis and treatment.
Area of Science:
- Genomics
- Human Genetics
- Molecular Biology
Background:
- Short-read sequencing limited the analysis of complex genomic regions, particularly segmentally duplicated loci.
- Previous methods could not resolve copy number, haplotype, and nucleotide-level variations within these challenging areas.
Purpose of the Study:
- To review how advanced sequencing technologies and analysis methods can characterize complex genetic loci.
- To highlight the extensive diversity within the spinal muscular atrophy-associated survival motor neuron (SMN) locus.
- To discuss the clinical translation of understanding population-level structural variation.
Main Methods:
- Long-read sequencing
- Paralog-aware variant calling
- Telomere-to-telomere (T2T) human genome assemblies
Main Results:
- Current technologies reveal extensive diversity in copy number (CN), structure, and gene conversion within the SMN locus.
- A nucleotide-level view of the SMN locus can refine prognostic accuracy beyond SMN2 CN.
- Variable treatment responses in spinal muscular atrophy may be explained by locus complexity.
Conclusions:
- Advanced genomic approaches enable the resolution of complex genetic regions previously inaccessible.
- Understanding structural variation at the SMN locus has potential clinical applications for spinal muscular atrophy.
- Methodologies used for the SMN locus can serve as a model for studying other complex human genetic regions.
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