Congenital myasthenic syndrome 17: genes and variants

Genes linked to Congenital myasthenic syndrome 17

• MUSK: Muscle, skeletal receptor tyrosine-protein kinase

  It organizes the postsynaptic neuromuscular junction by responding to agrin-LRP4 signaling and clustering acetylcholine receptors. Biallelic pathogenic variants cause congenital myasthenic syndrome, while autoantibodies against MuSK cause an important subtype of acquired myasthenia gravis.

  9 disease-causing and 237 uncertain variants in MUSK are linked to Congenital myasthenic syndrome 17.

• SCN4A: Sodium channel protein type 4 subunit alpha

  Its rapid sodium current initiates and propagates skeletal-muscle action potentials. Gain- and loss-of-function variants cause disorders of muscle excitability including sodium-channel myotonia, paramyotonia congenita, periodic paralysis, and some congenital myopathies.

  7 disease-causing and 85 uncertain variants in SCN4A are linked to Congenital myasthenic syndrome 17.

• LRP4: Low-density lipoprotein receptor-related protein 4

  It coordinates Wnt-related developmental signaling and serves as the agrin coreceptor that activates MuSK at the neuromuscular junction. Biallelic or dominant pathogenic variants can cause syndactyly, Cenani-Lenz syndactyly syndrome, or congenital myasthenic syndrome depending on the mechanism.

  4 disease-causing and 467 uncertain variants in LRP4 are linked to Congenital myasthenic syndrome 17.

• AGRN: Agrin

  At the neuromuscular junction, it organizes postsynaptic differentiation by activating the LRP4-MuSK signaling pathway and clustering acetylcholine receptors. Biallelic or dominant pathogenic variants can cause congenital myasthenic syndromes with fatigable muscle weakness.

  3 disease-causing and 12 uncertain variants in AGRN are linked to Congenital myasthenic syndrome 17.

Where Congenital myasthenic syndrome 17 variants cluster

• SCN4A III (positions 1013–1326): 4 of 7 disease-causing changes, 3.3× more than its size predicts.
• MUSK Cytoplasmic (positions 517–869): 6 of 9 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Congenital myasthenic syndrome 17

Which prediction tools work for Congenital myasthenic syndrome 17

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 86 out of 100
• SIFT: 83 out of 100
• phyloP: 70 out of 100

Same protein, different disease

• Hyperkalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (62 disease-causing).
• Paramyotonia congenita of Von Eulenburg is also caused by SCN4A variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (15 disease-causing).
• Potassium-aggravated myotonia is also caused by SCN4A variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (14 disease-causing).
• Hypokalemic periodic paralysis is also caused by SCN4A variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (11 disease-causing).
• Congenital myopathy 22A, classic is also caused by SCN4A variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (8 disease-causing).
• Cenani-Lenz syndactyly syndrome is also caused by LRP4 variants; they fall mostly in different places as the Congenital myasthenic syndrome 17 variants (9 disease-causing).

Diseases related to Congenital myasthenic syndrome 17

• Fetal akinesia deformation sequence, also linked to MUSK and SCN4A
• Amyotrophic lateral sclerosis, also linked to SCN4A
• Cardiac arrhythmia, also linked to SCN4A
• Sotos syndrome, also linked to SCN4A
• Hyperkalemic periodic paralysis, also linked to SCN4A
• Hypokalemic periodic paralysis, also linked to SCN4A
• Skeletal muscle channelopathy, also linked to SCN4A
• Epilepsy, also linked to SCN4A
• Paramyotonia congenita of Von Eulenburg, also linked to SCN4A
• Potassium-aggravated myotonia, also linked to SCN4A
• Cenani-Lenz syndactyly syndrome, also linked to LRP4
• Congenital myopathy 22A, classic, also linked to SCN4A

Frequently asked questions

Which genes are linked to Congenital myasthenic syndrome 17?

In CATVariant, Congenital myasthenic syndrome 17 is linked to 4 analyzed proteins: MUSK (Muscle, skeletal receptor tyrosine-protein kinase), SCN4A (Sodium channel protein type 4 subunit alpha), LRP4 (Low-density lipoprotein receptor-related protein 4) and AGRN (Agrin).

How many genetic variants are linked to Congenital myasthenic syndrome 17?

894 variants: 23 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 801 are of uncertain significance or have conflicting reports.

Which uncertain variants in Congenital myasthenic syndrome 17 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Congenital myasthenic syndrome 17?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 14 disease-causing and 43 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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