Spinal muscular atrophy

Spinal muscular atrophy is a recessive neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy (wasting away) and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness. There are five main subtypes of spinal muscular atrophy, and one's genotype does not always accurately predict which type of SMA will develop. In SMA patients, exon 7 of the SMN1 gene is homozygously absent in about 95% of cases; in the United States, 1 in every 5,000 - 10,000 people develop SMA, while around 1 in 50 are a carrier of the disease. SMA is most common in Caucasians, of whom 1 in 35 is a carrier, while other ethnicities may have carrier rates of between 1 in 40 to 1 in 120.Wikipedia

The region of chromosome 5 harboring the SMN1 gene is quite complex, and it contains a large number of highly similar paralogous sequences. A gene known as SMN2 lies centromeric to SMN1, and it is over 99% identical. There is one significant difference, however; in exon 7, at the third base of codon 280, the SMN1 gene harbors a (C) whereas the SMN2 gene has a (T). This C>T difference (rs4916, chr5:69,408,109) can therefore be used to differentiate the SMN1 gene from the SMN2 gene.[PMID 7813012]

In dbSNP, rs4916 is shown as having two alleles, (C) and (T). In actuality, this confounds SMN1 and SMN2, which is not surprising given that many genomic sequence assemblies have been unable to separate these two highly similar genes. For the purposes of carrier testing, a variety of techniques have been used to determine whether an individual carries two copies of SMN1 exon 7 (and is therefore not a carrier, like most individuals), or one copy (and is therefore a carrier), or zero copies (and is therefore predicted to develop spinal muscular atrophy).

The SMA Foundation sponsors research and assists in development of clinical trials for treatment of this condition. See also: OMIM 253300 and OMIM 600354

23andMe tests 11 SNPs in the SMN1 gene, giving them identification numbers instead of rs numbers; the risk allele is in the orientation used by 23andMe (and not necessarily the orientation used in dbSNP or SNPedia):

• rs104893930 = i5005734, risk allele A
• rs104893931 = i5005735, risk allele T
• rs77804083 = i5005733, risk allele A
• i5005732, risk allele A
• rs104893935 = i5005737, risk allele G
• rs104893933 = i5005739, risk allele T
• rs104893932 = i5005738, risk allele G
• rs75660264 = i5005728, risk allele T
• rs104893922 = i5005729, risk allele G
• rs76871093 = i5005727, risk allele T
• i5005741, risk allele G; it is unclear whether this one leads to SMA