Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy

In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and (c)BCD541 respectively) on normal and SMA chromosomes, This has enabled us to establish haplotypes with regard to SMN and (c)BCD541, and estimate their frequencies, on both types of chromosomes, Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of (c)BCD541, We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of (c)BCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of (c)BCD541 were identified, We could not confirm the hypothesis that the presence of more copies of (c)BCD541 is correlated to a less severe course of the disease, The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of (c)BCD541 were found to differ significantly between normal and SMA chromosomes, This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and (c)BCD541 should help clarify the role of (c)BCD541 in the pathogenesis of SMA.