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Master Thesis

Évaluation d'un haplotype associé à la duplication en cis du gène SMN1 : utilité pour le conseil génétique de l'amyotrophie spinale proximale

Abstract : Spinal muscular atrophy (SMA) is a genetic neuromuscular disease of varying severity, resulting from homozygous inactivation of the SMN1 gene. The detection of heterozygotes is based on the determination of the copy number of the SMN1 gene by quantitative techniques, such as QMPSF or MLPA. However, these techniques are faced with the existence of duplications in cis of the SMN1 gene in the general population. Indeed quantitative techniques do not allow us to know the phase of the SMN1 genes. Variants associated with duplications in cis of this gene have been identified in the Ashkenazi Jewish as well as in the Spanish population, suggesting a possible utility for genetic counseling. Objectives : We have replicated previous associations studies between two variants and duplications in cis of the SMN1 gene to a sample of the population of subjects analyzed at the Rouen University Hospital, in order to determine the parameters of sensitivity and specificity of this association in the population of our study. We investigated whether these variants could also be associated with duplications in cis of the SMN2 gene. Materials and methods : 199 subjects were classified into subgroups according to their genotype : 1+0, 1+1, 2+0, 2+1, 3+0, 2+2. We established their genotype at the loci of the two variants of interest, using a SNapShot technique and an Amplidex PCR/CE SMN1/2 kit. We considered 2 groups : the group "dup in cis" (genotypes 2+0, 2+1, 3+0, 2+2) and "absence of dup in cis" (genotypes 1+0 and 1+1). We evaluated the difference in the proportions of variants between the "dup in cis" and "absence of dup in cis" groups by an exact Fisher test and calculated the values of Se, Sp, VPP, VPN of the variant detection test. Results : The group "dup in cis" is significantly enriched in sought-after variants compared to the group "absence of dup in cis" (P = 1.6 . 10-7). Se is 17 %, Sp is 100 %, VPP 100% and NPV 92% to 94%. The variants sought are not associated with cis duplications of the SMN2 gene. Discussion and conclusion : The low value of Se does not make it possible to definitively eliminate a duplication in cis of the SMN1 gene in a relative carrying 2 copies of this gene, analyzed in the care of genetic counseling. It is therefore necessary to continue to analyze the spouse of a relative with SMA in the event of a parental plan. We could however integrate the search for variants into the analysis of the number of copies of the SMN1 gene in order to refine the calculation of the residual risk. We can consider sequencing or mapping techniques on long gDNA fragments (molecular combing, digital PCR, Bionano and Nanopore technologies) to assess the duplications in cis of the SMN1 gene while anticipating their possible lack of resolution to distinguish genes SMN1 and SMN2.
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Master Thesis
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Ferdi Kundul. Évaluation d'un haplotype associé à la duplication en cis du gène SMN1 : utilité pour le conseil génétique de l'amyotrophie spinale proximale. Médecine humaine et pathologie. 2020. ⟨dumas-02949211⟩



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