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

Previous reports have established that the telomeric copy of the survivalmotor neuron (SMNT) gene and the intact copy of the neuronal apoptosisinhibitory protein (NAIP) gene are preferentially deleted in patients withspinal muscular atrophy (SMA). Although deletions or mutations in the SMNTgene are most highly correlated with SMA, it is not clear to what extentNAIP or other genes influence the SMA phenotype, or whether a smallfraction of SMA patients actually have functional copies of both SMNT andNAIP. To evaluate further the part of SMNT in the development of SMA, weanalyzed 280 asymptomatic SMA family members for the presence or absence ofSMNT exons 7 and 8. We report the following observations: (i) 4% of thesample harbored a polymorphic variant of SMNT exon 7 that looks like ahomozygous deletion; (ii) approximately 1% of the parents are homozygouslydeleted for both exons 7 and 8; (iii) one asymptomatic parent lacking bothcopies of SMNT exons 7 and 8 displays a 'subclinical phenotype'characterized by mild neurogenic pathology; (iv) another asymptomaticparent lacking both SMNT exons showed no signs of motor neuron disorder byclinical and neurodiagnostic analyses. The demonstration of polymorphicvariants of exon 7 that masquerade as homozygous nulls, and theidentification of SMA parents who harbor two disease alleles, serve as acaution to those conducting prenatal tests with these markers.