Congenital Myasthenic Syndrome 21 via the SLC18A3 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 cases 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 21 or related disorders have been described in at least six different families with varied severity in presentation. The first two described cases include typical myasthenic clinical features of exercise intolerance, ptosis, ophthalmoplegia, hypotonia, feeding difficulties and facial weakness (O'Grady et al. 2016. PubMed ID: 27590285). However, a more severe presentation was observed in two siblings with retrognathia, severe hypotonia and distal arthrogryposis in all extremities, dislocated hips, respiratory failure, and genital abnormalities including undescended testes and micropenis (Aran et al. 2017. PubMed ID: 28188302). Prenatal onset was also described in two fetuses that were homozygous for a nonsense variant and presented with fetal akinesia, arthrogryposis, edema, and partial cleft palate (Hakonen et al. 2019. PubMed ID: 31059209). An additional two unrelated patients with biallelic variants in SLC18A3 presented with hypotonia, ptosis, poor weight gain, and apneic episodes (Lamond et al. 2021. PubMed ID: 33462016). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the SLC18A3 gene are associated with autosomal recessive congenital myasthenic syndrome 21. Missense variants and at least one nonsense variant have been reported to date; all variants were inherited from a carrier parent. Two large deletions encompassing the SLC18A3 gene and additional surrounding genes have also been reported (O'Grady et al. 2016. PubMed ID: 27590285). SLC18A3 is relatively intolerant to loss of function variants (Genome Aggregation Database).

The SLC18A3 gene encodes the vesicular acetylcholine transporter (VAChT), which transports acetylcholine into vesicles. Acetylcholine release from vesicles at the neuromuscular junction is necessary for both the central and peripheral nervous systems. Knockdown of VAChT in mice leads to myasthenic symptoms and cognitive defects (Prado et al. 2006. PubMed ID: 16950158), whereas knockout of VAChT in mice is lethal soon after birth due to cyanosis (de Castro et al. 2009. PubMed ID: 19635813). SLC18A3 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality).

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 and NGS copy number variant analysis.

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 SLC18A3 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).