Characterization of survival motor neuron (SMN(T)) gene deletions in asymptomatic carriers of spinal muscular atrophy

Previous reports have established that the telomeric copy of the survival motor neuron (SMN(T)) gene and the intact copy of the neuronal apoptosis inhibitory protein (NAIP) gene are preferentially deleted in patients with spinal muscular atrophy (SMA), Although deletions or mutations in the SMN(T) gene are most highly correlated with SMA, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMN(T) and NAIP, To evaluate further the part of SMN(T) in the development of SMA, we analyzed 280 asymptomatic SMA family members for the presence or absence of SMN(T) exons 7 and 8, We report the following observations: (i) 4% of the sample harbored a polymorphic variant of SMN(T) exon 7 that looks like a homozygous deletion; (ii) approximately 1% of the parents are homozygously deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both copies of SMN(T) exons 7 and 8 displays a 'subclinical phenotype' characterized by mild neurogenic pathology; (iv) another asymptomatic parent lacking both SMN(T) exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses, The demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor two disease alleles, serve as a caution to those conducting prenatal tests with these markers.