Congenital myasthenic syndromes: Achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: A study of 680 patients

Abstract

Congenital myasthenic syndromes (CMSs) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. Even though CMSs are genetic disorders, they are highly treatable, and the appropriate drug treatment depends on the underlying genetic defect. This highlights the importance of genetic testing in CMS. In recent years, the molecular basis of CMS has constantly broadened and disease-associated mutations have been identified in 14 genes encoding proteins of the neuromuscular junction. In the dawn of novel sequencing strategies, we report on our 14-year experience in traditional Sanger-based mutation screening of a large cohort of 680 independent patients with suspected CMS. In total, we identified disease-causing mutations in 299 patients (44%) of patients in various known CMS genes, confirming the high degree of genetic heterogeneity associated with the disease. Apart from four known founder mutations, and a few additional recurrent mutations, the majority of variants are private, found in single families. The impact of previously reported genotype-phenotype correlations on efficiency of genetic testing was analyzed in our population. Taking our experiment into account, we present our algorithm for genetic testing in CMS.

The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses

“…However, injection of G1709R mutant agrin, but not the WT protein, into the skeletal muscle of 4-wk-old rats perturbed the organization of NMJs, implying that the G1709R mutation may impair agrin-mediated signaling to maintain postnatal NMJs without affecting its ability to activate MuSK. Similar disturbances in this agrin-mediated signaling pathway could also be involved in the pathogenesis of other types of CMSs with unknown etiology because CMSs frequently present with postnatal onset (39). Therefore, uncovering the role that agrin plays in the postnatal maintenance of NMJs, apart from its role in MuSK activation, would not only deepen our understanding of NMJs but also pave the way toward finding new therapeutic targets for CMSs.…”

Splicing Aberrations in Congenital Myasthenic Syndromes

“…Due to heterogeneity of clinical manifestations and the underlying mechanisms, a large number of CMS cases are predicted to be undiagnosed or misdiagnosed [2,46,47]. CMS are not exceptional among Mendelian disorders from the viewpoint of germ line mutations.…”

Nicotinic acetylcholine receptors in human genetic disease

“…Mutations in genes encoding nicotinic acetylcholine receptors (CHRNA1, CHRNB1, CHRND, and CHRNE) are considered postsynaptic compartment CMSs and are responsible for up to 60% of all cases ( Table 1). 7 Deficient clustering of acetylcholine receptors at the end plate can be caused by mutations in MUSK, RAPSN, or DOK7, and others, causing CMSs with acetylcholine receptor deficiency and abnormal synaptic differentiation. 7 The single most common gene causing CMS is CHRNE, accounting for 20-25% of all cases, and 50% of those in which a molecular diagnosis can be established.…”

“…7 Deficient clustering of acetylcholine receptors at the end plate can be caused by mutations in MUSK, RAPSN, or DOK7, and others, causing CMSs with acetylcholine receptor deficiency and abnormal synaptic differentiation. 7 The single most common gene causing CMS is CHRNE, accounting for 20-25% of all cases, and 50% of those in which a molecular diagnosis can be established. 7 In slowchannel CMSs, gain-of-function mutations cause prolonged activations of the nicotinic acetylcholine receptors.…”