Familial Limb Girdle Myasthenic Syndrome via the AGRN Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from defects in presynaptic, synaptic, or postsynaptic proteins. Agrin is produced by the presynaptic neuron and released into the synaptic space and functions by activating MuSK. Clinically, a limb girdle pattern of muscle involvement makes DOK7 and AGRN-related CMS unique from other CMS. Age of onset typically ranges from birth to five years of age (Selcen et al. Ann Neurol 64:71-78, 2008; Beeson et al. Science 313:1975-1978, 2006). Thus far, one family has been reported with AGRN-associated familial limb girdle myasthenic syndrome (Huzé et al. Am J Hum Genet 85:155-167, 2009). The affected siblings reported having difficulty running beginning in childhood, mild facial weakness, unilateral ptosis, and thin thorax and pelvis. In adulthood, muscle function was stable although weakness worsened in one sibling during pregnancy and menstruation. Disorganization of the neuromuscular junction was evident in a muscle biopsy from an affected individual. Treatment with ephedrine was found to cause sustained improvement in muscle performance and endurance.

Abnormalities of proteins involved with neuromuscular transmission underlie familial limb girdle myasthenia syndrome, congenital myasthenia syndromes, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. Familial limb girdle myasthenic syndrome due to AGRN (OMIM 103320) variants is inherited as an autosomal recessive disorder. Affected members of the family with AGRN-associated CMS were homozygous for a c.5125G>C (p.Gly1709Arg) variant (Huzé et al. 2009).

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 AGRN gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).