Sotos syndrome: genes and variants

Genes linked to Sotos syndrome

• NSD1: Histone-lysine N-methyltransferase, H3 lysine-36 specific

  It regulates developmental transcription through chromatin modification, including H3K36 methylation. Haploinsufficiency causes Sotos syndrome with childhood overgrowth, characteristic facial features, and developmental delay, while somatic rearrangements occur in some leukemias.

  82 disease-causing and 288 uncertain variants in NSD1 are linked to Sotos syndrome.

• 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.

  1 disease-causing and 0 uncertain variants in SCN4A are linked to Sotos syndrome.

Where Sotos syndrome variants cluster

• NSD1 SET (positions 1942–2059): 22 of 82 disease-causing changes, 6.1× more than its size predicts.
• NSD1 PHD-type 4 (positions 2118–2165): 10 of 82 disease-causing changes, 6.8× more than its size predicts.
• NSD1 AWS (positions 1890–1940): 9 of 82 disease-causing changes, 5.8× more than its size predicts.
• NSD1 PHD-type 2 (positions 1590–1646): 9 of 82 disease-causing changes, 5.2× more than its size predicts.
• NSD1 PWWP 2 (positions 1756–1818): 7 of 82 disease-causing changes, 3.6× more than its size predicts.

Known disease-causing variants in Sotos syndrome

Showing 60 of 83.

Uncertain variants in Sotos syndrome that look disease-causing

Which prediction tools work for Sotos syndrome

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100

Same protein, different disease

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

Diseases related to Sotos syndrome

• Amyotrophic lateral sclerosis, also linked to SCN4A
• Cardiac arrhythmia, also linked to SCN4A
• Hyperkalemic periodic paralysis, also linked to SCN4A
• Acute myeloid leukemia, also linked to NSD1
• Hypokalemic periodic paralysis, also linked to SCN4A
• Congenital myasthenic syndrome 17, 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
• Weaver syndrome, also linked to NSD1
• Congenital myopathy 22A, classic, also linked to SCN4A

Frequently asked questions

Which genes are linked to Sotos syndrome?

In CATVariant, Sotos syndrome is linked to 2 analyzed proteins: NSD1 (Histone-lysine N-methyltransferase, H3 lysine-36 specific) and SCN4A (Sodium channel protein type 4 subunit alpha).

How many genetic variants are linked to Sotos syndrome?

509 variants: 83 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 288 are of uncertain significance or have conflicting reports.

Which uncertain variants in Sotos syndrome look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NSD1 R1660H and NSD1 R1914H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Sotos syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 70 disease-causing and 248 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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