Long Read Analysis in Spinal Muscular Atrophy - LOREASI

University Hospital, Rouen

Status: Enrolling

Conditions: Spinal Muscular Atrophy (SMA)

Treatments: Genetic: blood sample

Study type: Interventional

Funder types: Other

Identifiers

NCT07332702

2023/0154/HP

Details and patient eligibility

About

Spinal Muscular Atrophy (SMA) is a severe neuromuscular disease caused by deletion of the SMN1 gene, with the most severe form leading to death in children without treatment. Genetic counselling to detect couples where both partners are carriers is particularly important. In some countries, preconception screening is offered. However, some carriers escape detection due to the existence of two copies of the SMN1 gene side-by-side (2+0 genotype). Currently, no molecular genetic methods used for diagnostic purposes can detect these 2+0 genotypes, which pose a significant challenge in genetic counselling.

This study aims to use new technologies based on the analysis of ultra-long molecules to detect side-by-side duplications of the SMN1 gene to detect heterozygous subjects not identified by current techniques and improve genetic counselling.

Full description

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.

Enrollment: 27 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Prevention

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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27 participants in 2 patient groups

Control group

Experimental group

Description:

subjects carrying 1 or 3 copies of the SMN1 gene and a variable number of copies of the SMN2 gene

Treatment:

Genetic: blood sample

Test group

Experimental group

Description:

subjects carrying a 2+0 genotype (two copies of the SMN1 gene in cis on one allele and a deletion on the other allele)

Treatment:

Genetic: blood sample