Best practice guidelines for molecular analysis in spinal muscular atrophy

With a prevalence of approximately 1/10 000, and a carrier frequency of 1/4 0-1/60 the proximal spinal muscular atrophies (SMAs) are among the most fre quent autosomal recessive hereditary disorders. Patients can be classified clinically into four groups: acute, intermediate, mild, and adult (SMA type s I, II, III, and IV, respectively). The complexity and instability of the genomic region at chromosome 5q13 harbouring the disease-causing survival m otor neuron 1 (SMN1) gene hamper molecular diagnosis in SMA. In addition, a ffected individuals with SMA-like phenotypes not caused by SMN1, and asympt omatic individuals with two mutant alleles exist. The SMN gene is present i n at least one telomeric (SMN1) and one centromeric copy (SMN2) per chromos ome in normal (non-carrier) individuals, although chromosomes containing mo re copies of SMN1 and/or SMN2 exist. Moreover, the two SMN genes (SMN1 and SMN2) are highly homologous and contain only five base-pair differences wit hin their 3 ' ends. Also, a relatively high de novo frequency is present in SMA. Guidelines for molecular analysis in diagnostic applications, carrier detection, and prenatal analysis using direct and indirect approaches are described. Overviews of materials used in the molecular diagnosis as well a s Internet resources are included.