Diagnosing a Neuro-muscular Disorder

We just read a recent publication that used Avadis NGS in the process of diagnosing the case of a Japanese boy suffering from a neuromuscular disorder. Here is a link to the paper. The case is summarized below:

The boy was born in a family with no history of neuromuscular disease. He experienced transient breath-holding episodes shortly after birth. At 11 months of age, 30-second-long episodes of suspended breathing with increase in muscle tension appeared. These episodes were severe enough to suspect epileptic seizures, but EEG recordings did not support this hypothesis. At the age of two, the boy started having myotonic attacks (slow relaxation of the muscles after voluntary contraction, so you have trouble releasing your grip after gripping something, or rising from a sitting position etc) that persisted for several minutes, hours, or even days, and created difficulties in standing, walking and mobility. After 7 years and 8 months of age, paralytic episodes appeared that occurred several times a year thereafter.

Based on these and various other physical characteristics, he was suspected to have something called Schwartz-Jampel Syndrome; this is a recessive disorder and caused when both copies of the HSPG2 gene go bad. The authors sequenced the exonic regions of this gene (first enriching using SureSelect, then sequencing on SOLiD, then using Avadis to call SNPs) to check for mutations, and found only 3 homozygous SNPs, all of which were registered in dbSNP 134 with no knowledge of clinical significance and fairly high allele frequencies. On this basis, they ruled out Schwartz-Jampel Syndrome conclusively (it is unclear whether or not the authors checked for compound heterozygosity). Here is a snapshot of the Avadis NGS Genome Browser showing the HSPG2 gene.

They then investigated other genes known to be involved in neuromuscular signaling, and found a Non-Synonymous SNP in the SCN4A gene; neither of the parents had this SNP, so it was a de-novo mutation. Based on this a diagnosis of a type of Sodium Channelopathy was made and some appropriate therapies were applied with some improvement.