Long Read Analysis in Spinal Muscular Atrophy - LOREASI

Official title

Detection of Cis Duplications of the SMN1 Gene Using Long-read Analysis to Address a Major Issue in Genetic Counseling for Spinal Muscular Atrophy

Overview

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.

Detailed 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.

Interventions

• Genetic blood sample
  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 outcome measures

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

Secondary outcome measures (1)

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

Eligibility 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

France · 1 center

• CHU Rouen — Rouen

Identifiers

NCT: NCT07332702 · 2023/0154/HP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗