The SMN locus in the T2T era: Structure, gene conversion, and clinical implications

Long-read sequencing, paralog-aware variant calling, and telomere-to-telomere (T2T) human genome assemblies now enable the resolution of copy-, haplotype-, and nucleotide-level complexities in segmentally duplicated loci, which were previously inaccessible with short-read sequencing. In this review, we highlight how current technologies and analysis methods reveal extensive diversity in copy number (CN), structure, and gene conversion within the spinal muscular atrophy-associated survival motor neuron (SMN) locus. We summarize how understanding population-level structural variation could be translated into clinical practice, where a nucleotide-level view of the SMN locus may refine prognostic accuracy beyond SMN2 CN and explain variable treatment responses. Finally, we discuss how the approaches and methodologies required to study the SMN locus may be applied elsewhere, providing a scaffold to characterize other complex human genetic regions.