Biomedical Engineering Reference
In-Depth Information
Chapter 6
Diagnosis of Inherited Neuromuscular
Disorders by Next-Generation-Sequencing
Inherited neuromuscular disorders (NMD) form a group of genetic diseases that
result in long-term disability. The total incidence of NMD is greater than 1 in 3,000
and comprises a group of more than 200 monogenic disorders (Emery 1991 ). For
about half of the cases, the molecular cause has not been identifi ed. An extensive
clinical evaluation with complementary gene-by-gene testing is often required to
reach an exact diagnosis. Due to the presence of genetic heterogeneity and lack of
segregation in sporatic cases, reaching a diagnosis is challenging, lengthy, and
expensive. The genetic heterogeneity can be demonstrated by the number of genes
involved in specifi c subgroups of NMD, namely, hereditary sensorimotor neuropa-
thies (HSMN; 50 genes) and congenital muscular dystrophies (12 genes; North
2008 ; Valencia et al. 2013 ). In other instances, some NMD genes are very large and
are not sequenced completely because it is costly and labor-intensive to sequence by
the Sanger method. For the patient, this gene-by-gene approach increases the num-
ber of tests that are required, thus, delaying the diagnosis and exposing the patient
to unnecessary investigations and treatments, precluding the full benefi t of a tar-
geted approach to treatment, and increasing recurrence risk in the families (Vasli
et al. 2012 ).
Next-generation-sequencing (NGS) has been shown to interrogate multiple
genes in parallel. This approach has been mainly used to identify novel disease
genes in a research setting. Recently, several clinical laboratories, including
Emory Genetics Laboratory (EGL) and Boston Children's DNA Diagnostic labo-
ratories, have translated NGS and offer clinical muscular dystrophy panels. In
the following sections, we summarize data that demonstrate the application of
NGS to address genetic heterogeneity and large target sequencing intervals in
NMD examples.
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