DE-NOVO REARRANGEMENTS FOUND IN 2-PERCENT OF INDEX PATIENTS WITH SPINAL MUSCULAR-ATROPHY - MUTATIONAL MECHANISMS, PARENTAL ORIGIN, MUTATION-RATE, AND IMPLICATIONS FOR GENETIC-COUNSELING

Spinal muscular atrophy (SMA) is a relatively common autosomal recessi ve neuromuscular disorder. We have identified de novo rearrangements i n 7 (similar to 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric c opy of the survival motor neuron (SMN) gene (telSMN), in two cases acc ompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, wit h loss of markers Ag1-CA and C212, which are near the 5' ends of the S MN genes. In one case, an interchromosomal rearrangement involving bot h the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intr achromosomal deletion or gene conversion. In six of the seven cases, t he de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allo wed us to estimate for the first time the mutation rate for a recessiv e disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived a t in a proband-based approach, compares well with the rate of 0.9 x 10 (-4) expected under a mutation-selection equilibrium for SMA. These fi ndings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype a nalysis in combination with direct SMN-gene deletion testing in SMA fa milies.