The presence of SMN1 exon 7 does not entirely exclude a diagnosis of SMA. Although the absence of both copies of the SMN1 gene is a very reliable and sensitive assay for the majority of SMA patients, about 6% of affected patients have other types of mutations in the SMN1 gene that will not be detected by PCR deletion testing.34 Most of these patients will be compound heterozygotes, with one SMN1 allele deleted and the other allele with a point mutation or other small insertion or deletion. If the clinical suspicion remains high after a negative deletion test, then dosage carrier testing to determine whether there is a single copy of SMN1 should be considered. A dosage testing result of two copies of the SMN1 gene greatly reduces the likelihood of SMA.
The carrier test has two limitations. The first is the presence of de novo mutational events in the SMN1 gene. The de novo mutation rate for this gene has been observed to be approximately 2%, which is high when compared to most autosomal recessive disorders.35 The second limitation of the carrier test is the finding of two SMN1 genes on a single chromosome. The allele frequency of the 2-copy SMN1 chromosome is approximately 2% in the general population. The finding of two SMN1 genes on a single chromosome has serious genetic counseling implications, because a carrier individual with two SMN1 genes on one chromosome would have the same dosage result as a non-carrier with two SMN1 gene copies on each chromosome 5. Approximately 5% of parents of a single affected SMA child have two SMN1 gene copies by dosage analysis. Thus, although, the finding of normal dosage significantly reduces the risk of being a carrier,there is still a recurrence risk of future affected offspring for individuals with two SMN1 gene copies. Thus, risk assessment calculations using Bayesian analysis are essential for the proper genetic counseling of SMA families (see chapter 5).
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