Spinal muscular atrophy and next gen sequencing – can it really be that difficult?

Peter Field1, Melinda Richter1, Nicole Martin1

1 Virtus Diagnostics – QFG Genetics, Level 1 Boundary Court, 55 Little Edward Street, Brisbane, QLD, 4000

Spinal Muscular Atrophy (SMA) is a severe life limiting autosomal recessive condition with a carrier rate of approximately 1 in 40 to 1 in 60.  Current testing for carrier and affected status relies on the few base pair differences between the SMN1 gene and the SMN2 pseudogene.  These base pair differences allow for selective annealing of probes prior to MLPA or real time PCR for two successful methods of carrier screening.

Next Generation Sequencing (NGS) should be able to distinguish these base pair differences and allow the user to identify carrier from affected from normal samples, but this is not the case.  The first problem is trying to sequence a deletion of an exon, the entire amplicon used in NGS is not there and no variant is reported.  The sequence homology between the two genes is over 99.9%, so you rely on the software to capture those differences.  The software preferentially analyses SMN2 prior to SMN1 leading to amplicons attributed to the incorrect location.

There has been a published method for identifying carriers with NGS but as we identified, this is not necessarily accurate and could lead to misdiagnosis for the unaware investigator.


Molecular Genetics Supervisor at QFG Genetics

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