Two independent mutations of the SMN1 gene in the same spinal muscular atrophy family branch: lessons for carrier diagnosis

We present the results of carrier studies in 33 relatives of the paternal branch of a spinal muscular atrophy patient with homozygous absence of the SMN1 gene. Once linkage and quantitative analyses were performed, a number of first-, second- and third-degree relatives were identified as carriers given that they shared the at-risk haplotype and showed one SMN1 copy. In the fourth-degree relatives, linkage analysis demonstrated discordance with the quantitative results because the members with one copy were carriers of the mutation, but in a different haplotype background. We concluded that two independent mutations were present in this branch of the family. Furthermore, the combination of both methods of analysis allowed us to identify carriers with two SMN1 genes in one chromosome and none in the remaining chromosome. Carrier testing in spinal muscular atrophy should be performed by employing both quantitative and linkage analyses in order to guarantee accurate carrier identification.