Familial Limb Girdle Myasthenia Syndrome via the DOK7 Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from defects in presynaptic, synaptic, or post-synaptic proteins. The protein encoded by DOK7 is essential for neuromuscular synaptogenesis due to its role in inducing autophosphorylation of the skeletal muscle receptor-like tyrosine kinase (MuSK), a key protein involved in postsynaptic differentiation (Okada et al. Science 312:1802-1805, 2006). Variants in DOK7 result in small neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function (Beeson et al. Science 313:1975-1978, 2006). Electron microscopy studies of patients with DOK7 variants shows destruction and remodeling of end plates at neuromuscular junctions (Selcen et al. Ann Neurol 64:71-87, 2008). Clinically, a limb girdle pattern of muscle involvement makes DOK7-related CMS unique from other forms of CMS. Age at onset typically ranges from birth to five years of age (Selcen et al. 2008) with onset in a minority of patients occurring beyond age five years (Beeson et al. 2006). The latter study found that the most common clinical presentation was difficulty in walking after initially achieving normal walking milestones. In a cohort of sixteen DOK7 positive patients characterized by Selcen et al. (2008), disease severity and rate of progression was variable; some patients exhibited mild static weakness limited to limb girdle muscles, while others had severe generalized disease with muscle atrophy. Ten of the sixteen patients had intermittent worsening of symptoms lasting from days to weeks. All patients reported fatigue on exertion and proximal muscle weakness. Other common features among the sixteen patients included ptosis (14/16), facial weakness (13/16), bulbar symptoms (11/16), and respiratory difficulties (13/16).

Familial limb girdle myasthenic syndrome due to DOK7 gene variants (OMIM 254300) is inherited as an autosomal recessive disorder. In a cohort of 21 patients, Beeson et al. (2006) found 16 to have the same exon 7  variant (c.1124_1127dupTGCC). Fourteen of 16 patients reported by Selcen et al. (2008) had a least one allele with the c.1124_1127dupTGCC variant, and four were found to have heterozygous gross alterations (intron inclusion or exon skipping) undetectable in genomic DNA.

DOK7, AGRN, and GFPT1 variants are the only known cause of familial limb girdle myasthenic syndrome. Clinical sensitivity should be high for patients meeting rigorous clinical, histopathological, and electrophysiological criteria.

This test provides full coverage of all coding exons of the DOK7 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.