Long Read Analysis in Spinal Muscular Atrophy - LOREASI

Spinal Muscular Atrophy (SMA) is a severe autosomal recessive neuromuscular disease, with the most severe form leading to death in children without treatment. Genetic counseling to detect couples where both partners are heterozygous is particularly important. In some countries, preconception screening is offered. However, some individuals' heterozygous status escape detection due to the existence of a cis duplication of the SMN1 gene on the second allele (\[2+0\] genotype). Currently, no molecular genetic methods used for diagnostic purposes can detect these \[2+0\] genotypes, which poses a significant challenge in genetic counseling.

The SMN1 gene, responsible for SMA, is located in the 5q11q13 region, which remains poorly understood in the human reference genome ("dark region"). The architecture of this inverted duplicated region favors recombination events that lead to deletions, duplications, and gene conversions. The SMN1 gene, located in the telomeric region, has a very homologous copy, the SMN2 gene, located in the centromeric region. The lack of detailed knowledge about duplication events hinders the development of molecular tools aimed at improving genetic counseling.

This study aims to use new technologies based on the analysis of ultra-long molecules to detect cis duplication of the SMN1 gene. We will assess the usefulness of optical mapping (Bionano) to analyze this complex region.

• blood sample (Genetic): For subjects who agree to participate in the study, a blood sample will be taken (2x5 mL on EDTA) and sent the same day at 4°C to the genetics laboratory at Rouen University Hospital using a carrier that guarantees delivery on D+1

Primary outcomes

• Ability to identify a [2+0] SMN1 genotype [From enrollment until the end of the analyses (36 months)]

Secondary outcomes

• Ability to perform assembly of ultra-long molecules of DNA [From enrollment until the end of the analyses (36 months)]

Sex: All, ages: 18 Years to any

Inclusion Criteria

• Adult Subject:

* Subject with either:

  * 1 or 3 copies of the SMN1 gene (control group) and a variable number of copies of the SMN2 gene
  * 2 copies of the SMN1 gene in cis (2+0 genotype) (test group)
* Affiliation to French health insurance
* Signed consent form

Exclusion Criteria

* Pregnant or breastfeeding women
* Individuals deprived of liberty by an administrative or judicial decision, or those under guardianship or curatorship