ArticleGenome medicine2025
Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy.
Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Article
- Aggregate variant calling using short reads enables population and disease studies for paralogous genes.HGG advances · 2026Article
- Characterisation of the SMN1/2 locus using a highly specific variant caller on whole-genome sequence data from 500,000 individuals.European journal of human genetics : EJHG · 2026Article
- Ensilication preserves high-molecular weight native DNA for clinical long-read sequencing.Genome biology · 2026Article
- Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening.BMC medical genomics · 2026Article
- Accessing medically relevant complex regions with a pangenome graph of 20 near-complete Japanese haplotypes.Nature communications · 2026Article
- Multimodal characterisation of the SMN locus in SMA: copy number quantification and hybrid gene identification.NPJ genomic medicine · 2026Article
- Multiplatform comparisons and annotation of structural variants highlight the utility of the T2T reference genome in human diagnostics.GigaScience · 2026Article
- Gene-Pseudogene Inversions as a Hidden Source of Missing Heritability.medRxiv : the preprint server for health sciences · 2025Article
- Comprehensive analysis acrossiScience · 2025Article
- A de novo deletion underlying spinal muscular atrophy: implications for carrier testing and genetic counseling.Human molecular genetics · 2025Article
- Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy.Genome medicine · 2025Article
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Authors and funding
20 authors.
Funding
Abstract
backgroundThe complex 2 Mb survival motor neuron (SMN) locus on chromosome 5q13, including the spinal muscular atrophy (SMA)-causing gene SMN1 and modifier SMN2, remains incompletely resolved due to numerous segmental duplications. Variation in SMN2 copy number, presumably influenced by SMN1 to SMN2 gene conversion, affects disease severity, though SMN2 copy number alone has insufficient prognostic value due to limited genotype-phenotype correlations. With advancements in newborn screening and SMN-targeted therapies, identifying genetic markers to predict disease progression and treatment response is crucial. Progress has thus far been limited by methodological constraints.
methodsTo address this, we developed HapSMA, a method to perform polyploid phasing of the SMN locus to enable copy-specific analysis of SMN and its surrounding genes. We used HapSMA on publicly available Oxford Nanopore Technologies (ONT) sequencing data of 29 healthy controls and performed long-read, targeted ONT sequencing of the SMN locus of 31 patients with SMA.
resultsIn healthy controls, we identified single nucleotide variants (SNVs) specific to SMN1 and SMN2 haplotypes that could serve as gene conversion markers. Broad phasing including the NAIP gene allowed for a more complete view of SMN locus variation. Genetic variation in SMN2 haplotypes was larger in SMA patients. Forty-two percent of SMN2 haplotypes of SMA patients showed varying SMN1 to SMN2 gene conversion breakpoints, serving as direct evidence of gene conversion as a common genetic characteristic in SMA and highlighting the importance of inclusion of SMA patients when investigating the SMN locus.
conclusionsOur findings illustrate that both methodological advances and the analysis of patient samples are required to advance our understanding of complex genetic loci and address critical clinical challenges.
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