Type I spinal muscular atrophy is a devastating neurodegenerative disease with onset by 6 months of age and death by the age of two years, usually due to respiratory infection. Homozygous deletions of the SMNtel, but not the SMNcen, gene have been identified in 95% of SMA patients. These genes map to chromosomes 5p13 and are within a large inverted repeat which includes the NAIP gene, the telomeric copy of which is also deleted in a large proportion of SMA type I patients.
We have investigated a family, in which there had been an affected child who was homozygously deleted for SMNtel and NAIP exon 5, to determine the disease status of a fetus. Analysis of cultured amniocytes indicated that the fetus is not homozygously deleted for SMNtel or NAIP. Several markers in the SMN/NAIP region were used to rule out maternal contamination of the amniocytes. During this process, it was noted that the fetus and the affected child had similar haplotypes but the paternal chromosome in the affected child carried a recombination. This recombination is associated with a deletion of several alleles of two multiallelic markers, AG1 and CATT. Dosage analysis revealed that the mother is an SMA earner with only one copy of SMNtel. In contrast, the father has 2 copies of SMNtel, suggesting that he is not a carrier of an SMNtel deletion. Rather, the paternal allele in the affected child probably resulted from a recombination event during which there was simultaneous deletion of the SMNtel gene along with some AG1 and CATT alleles. These data significantly lower the SMA recurrence risk for this family. This case highlights the necessity of using dosage information when assessing recurrence risk in SMA families.
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McGowan-Jordan, J., Zeesman, S., Whelan, D. et al. Detection of a de novo mutation in a family with SMA Type I: The importance of dosage testing. Genet Med 2, 106 (2000). https://doi.org/10.1097/00125817-200001000-00201