| Domain | Best-supported quantitative/current finding | Evidence type/year | Ontology-ready terms |
|---|---|---|---|
| Identifiers | Sotos syndrome; OMIM 117550; MONDO:0019349; synonym: cerebral gigantism syndrome | Curated disease resources, 2025 | MONDO:0019349; Sotos syndrome |
| Cardinal phenotypes | Distinctive facial appearance, learning/developmental disability, and childhood overgrowth occur in ≥90% of molecularly confirmed cases; overgrowth is not obligatory | Human cohort, 2005; clinical synthesis, 2025 | HP:0001513 Overgrowth; HP:0000256 Macrocephaly; HP:0001263 Global developmental delay; HP:0001622 Premature birth is **not** cardinal |
| Neonatal features | Hypotonia ~75%, poor feeding ~70%, and neonatal jaundice ~65% | Aggregated clinical cohorts, 2025 | HP:0001252 Hypotonia; HP:0011968 Feeding difficulties; HP:0000952 Jaundice |
| Growth and skeletal findings | Bone age is advanced in ~75–80% of prepubertal children; scoliosis occurs in ~30%; height often approaches the normal range after puberty, while macrocephaly usually persists | Human natural-history synthesis, 2005–2025 | HP:0005616 Accelerated skeletal maturation; HP:0002650 Scoliosis; HP:0000256 Macrocephaly |
| Neurologic and behavioral findings | Non-febrile seizures occur in ~25%; intellectual impairment varies from mild to severe and is generally stable; ASD, ADHD, anxiety, expressive-language difficulty, and sleep disturbance are recurrent | Human cohorts and review, 2024–2025 | HP:0001250 Seizure; HP:0001249 Intellectual disability; HP:0000729 Autistic behavior; HP:0007018 Attention deficit hyperactivity disorder; HP:0000739 Anxiety |
| Cardiovascular and renal complications | Historical cardiac-anomaly estimates are 15–40%; a selected 2024 molecularly confirmed cohort found heart defects in 27/45 (60%). Renal anomalies occur in ~15% | Human observational cohorts, 2024–2025 | HP:0001627 Abnormal heart morphology; HP:0000077 Abnormal renal morphology; UBERON:0000948 heart; UBERON:0002113 kidney |
| Genetics and inheritance | Heterozygous NSD1 loss-of-function variants or 5q35 deletions cause autosomal-dominant disease; ~95% are de novo and ~5% inherited. An affected individual has a 50% transmission risk | Human molecular cohorts and curated synthesis, 2005–2025 | NSD1; HGNC:14234; 5q35.3; HP:0000006 Autosomal dominant inheritance |
| Variant spectrum | Truncating, frameshift, nonsense, splice, pathogenic functional-domain missense, partial-gene deletion, and whole-gene/5q35 microdeletion variants occur. Microdeletions correlate with less prominent overgrowth and more severe learning disability | Human genotype–phenotype cohorts, 2005–2023 | SO:0001587 stop gained; SO:0001589 frameshift variant; SO:0001574 splice acceptor variant; SO:0000159 deletion |
| Molecular mechanism | NSD1 haploinsufficiency reduces H3K36 methyltransferase dosage, disturbing H3K36me1/2-directed DNA methylation and PRC2 regulation; human profiling shows promoter hypomethylation and dysregulation of bivalent developmental and neural-synapse genes | Human multi-omics plus biochemical evidence, 2011–2022 | GO:0046975 histone H3K36 methyltransferase activity; GO:0016571 histone methylation; GO:0006306 DNA methylation; GO:0040029 regulation of gene expression, epigenetic; GO:0000785 chromatin |
| Molecular diagnosis | Diagnosis is established by a heterozygous pathogenic/likely pathogenic NSD1 variant or NSD1-encompassing deletion. Testing may use sequencing plus deletion/duplication analysis, CMA, an overgrowth panel, exome, or genome sequencing | Clinical diagnostic guidance, 2023–2025 | NCIT:C15709 Genetic Testing; NCIT:C17609 Chromosomal Microarray; NCIT:C101295 Whole Exome Sequencing; NCIT:C101294 Whole Genome Sequencing |
| Recent diagnostic development | Among 1,530 clinically suspected cases, 292 (19.1%) had NSD1 findings; 115 novel intragenic variants, nine partial deletions, and 13 whole-gene microdeletions were identified. Twenty-five of 32 assessed missense VUS (78.1%) were reclassified as likely pathogenic or likely benign | Human diagnostic cohort, 2023 | NCIT:C118466 Variant Classification; NCIT:C17248 Mutation Analysis; NSD1 |
| Tumor risk and screening | Tumors are reported in approximately 3%; sacrococcygeal-teratoma/neuroblastoma risk is ~1%. Expert guidance does not recommend routine cancer screening or routine renal ultrasound because risk is insufficient and Wilms-tumor risk is not significantly increased | Cohort synthesis and expert guidance, 2017–2025 | HP:0002664 Neoplasm; NCIT:C15709 Genetic Testing; NCIT:C16210 Cancer Screening |
| Treatment and trials | No disease-modifying therapy is established. Care is individualized and supportive: developmental and educational services, speech/AAC, PT/OT, feeding support, behavioral/psychiatric care, antiseizure treatment, and organ-specific intervention. No relevant disease-modifying Sotos trial was identified | Expert guidance and trial-registry search, 2024–2025 | NCIT:C15308 Supportive Care; NCIT:C15986 Physical Therapy; NCIT:C16020 Occupational Therapy; NCIT:C17149 Speech Therapy; NCIT:C61577 Anticonvulsant Therapy |
| Mouse model | Nsd1+/− mice have ~50% lower cortical Nsd1 expression, impaired social novelty and fewer pup ultrasonic vocalizations, but no overgrowth, macrocephaly, gross cortical enlargement, or active-place-avoidance deficit. Nsd1−/− embryos die by approximately E10.5 with early patterning/forebrain abnormalities | Genetically engineered mouse, 2020–2021 | NCBITaxon:10090 Mus musculus; GO:0009790 embryo development; GO:0021987 cerebral cortex development; CL:0000540 neuron |


*Table: Concise evidence matrix summarizing the best-supported clinical, genetic, mechanistic, diagnostic, management, and model-organism findings for Sotos syndrome. Ontology-ready terms are included to support structured knowledge-base annotation.*