Congenital Myasthenic Syndrome 24 via the MYO9A Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness (Vanhaesebrouck and Beeson. 2019. PubMed ID: 31361628; Abicht et al. 2016. PubMed ID: 20301347). Some neuromuscular junction genes can result in a more severe presentation of fetal akinesia, intrauterine growth retardation, arthrogryposis, lung hypoplasia, cleft palate, and cryptorchidism (Pergande et al. 2020. PubMed ID: 31680123). Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running. Most patients present prior to 2 years of age, although rare exceptions have been reported (Vanhaesebrouck and Beeson. 2019. PubMed ID: 31361628; Abicht et al. 2016. PubMed ID: 20301347). Symptoms are extremely variable, and are in some case induced by febrile illness, infection, or excitement. Life threatening respiratory crises may occur in affected neonates or older children. CMS may be differentiated from myasthenia gravis, an acquired autoimmune disorder, by earlier age at onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies.

Congenital myasthenic syndrome 24 or related disorders have been described in at least five individuals from four different families. Three individuals presented with classic features of CMS including ptosis, respiratory failure, hypotonia, proximal and distal muscle weakness, and difficulty swallowing and chewing (O'Connor et al. 2016. PubMed ID: 27259756). An additional individual with compound heterozygous variants presented with distal arthrogryposis, contractures of knees, camptodactylyl, and talipes equinovarus (Bayram et al. 2016. PubMed ID: 26752647). A patient homozygous for a nonsense variant presented with more severe features of hydrocephalus and fetal akinesia (Maddirevula et al. 2018. PubMed ID: 30237576). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the MYO9A gene are associated with autosomal recessive congenital myasthenic syndrome 24. Missense variants and one nonsense variant have been reported to date and have been inherited from a carrier parent. No structural variants have been reported.

The MYO9A gene encodes an unconventional myosin protein which is part of a family of molecular motors. MYO9A appears to be of particular importance in neuronal branching and axon guidance and appears to be required for formation of the neuromuscular junction during development (O'Connor et al. 2016. PubMed ID: 27259756). Knockdown of MYO9A in zebrafish resulted in abnormal movement and tail curvature (O'Connor et al. 2016. PubMed ID: 27259756). MYO9A has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality). MYO9A is relatively intolerant to loss-of-function variants (gnomAD).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature. Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the MYO9A gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).