| Domain | Specific finding | Evidence type | Primary source | PMID if known | URL | Citation ID |
|---|---|---|---|---|---|---|
| Identifiers | Smith–Magenis syndrome (SMS) is identified as **OMIM #182290**; defined as a complex genetic disorder with distinctive physical features, developmental delay, cognitive impairment, and a behavioral phenotype. | Review | Rinaldi 2022 *Genes* |  | https://doi.org/10.3390/genes13020335 | (pqac-00000022) |
| Genetics | SMS is caused in ~**90%** of cases by **17p11.2 deletions** including **RAI1**, and in ~**10%** by **pathogenic RAI1 variants**; RAI1 is dosage-sensitive and acts as a transcriptional regulator. | Review | Rinaldi 2022 *Genes* |  | https://doi.org/10.3390/genes13020335 | (pqac-00000022) |
| Genetics | About **10%** of SMS patients carry an **RAI1 mutation**; the recurrent **~3.7 Mb deletion** is observed in about **70–80% of deleted patients**. | Review | Falco 2017 *Application of Clinical Genetics* |  | https://doi.org/10.2147/TACG.S128455 | (pqac-00000002) |
| Prevalence | Estimated prevalence/birth incidence is **1 in 15,000 to 1 in 25,000**, with no sex predominance reported. | Review | Rinaldi 2022 *Genes* |  | https://doi.org/10.3390/genes13020335 | (pqac-00000022) |
| Prevalence | Epidemiology estimates: prevalence **1/15,000** and birth incidence **1/25,000**. | Review | Falco 2017 *Application of Clinical Genetics* |  | https://doi.org/10.2147/TACG.S128455 | (pqac-00000002) |
| Genetics/Inheritance | Deletions or mutations are usually **de novo**; recurrence risk from parental gonadal mosaicism is **<1%**, rising to **3%–5%** if a parent is mosaic for the deletion or an RAI1 variant. | Human cohort | Gouard 2021 *Clinical Genetics* |  | https://doi.org/10.1111/cge.13906 | (pqac-00000004) |
| Key phenotypes | In a **47-patient European cohort** with 17p11.2 deletions: prenatal anomalies **15%**, reduced fetal movements **50%**, ophthalmologic problems **89%**, scoliosis **43%**, deafness **32%**, obstipation **45%**, epilepsy **2%**, behavioral problems **84%**, and night-time awakenings **86%**. | Human cohort | Gouard 2021 *Clinical Genetics* |  | https://doi.org/10.1111/cge.13906 | (pqac-00000004) |
| Key phenotypes | In the same cohort, among patients older than 10 years, **>60%** were overweight; heart defects included **6.5% tetralogy of Fallot** and **6.5% pulmonary stenosis**; all had learning difficulties, but **10%** had IQ in the normal range. | Human cohort | Gouard 2021 *Clinical Genetics* |  | https://doi.org/10.1111/cge.13906 | (pqac-00000004) |
| Temporal development | Clinical/behavioral phenotype often becomes recognizable between **18–36 months**; maladaptive behaviors may start around **18 months**, and the overall neurobehavioral phenotype is usually recognizable from the **second year of life**. | Human cohort/review | Gouard 2021 *Clinical Genetics*; Falco 2017 *Application of Clinical Genetics* |  | https://doi.org/10.1111/cge.13906 ; https://doi.org/10.2147/TACG.S128455 | (pqac-00000004, pqac-00000002) |
| Registry findings | International SMS registry (**n=82**): **35%** had hearing loss, **66%** had otitis media history, and **62%** had pressure-equalization (PE) tubes. | Registry | Brennan 2024 *JSLHR* |  | https://doi.org/10.1044/2023_JSLHR-23-00179 | (pqac-00000016) |
| Registry findings | In the same registry, **60%** communicated using speech; **79%** spoke first words at/after **24 months**; **92%** combined words at/after **36 months**; **41%** used sign language before speech. | Registry | Brennan 2024 *JSLHR* |  | https://doi.org/10.1044/2023_JSLHR-23-00179 | (pqac-00000016) |
| Registry findings | More detailed registry results: mean age at first PE tube placement **24 months** (range **6–72**), mean **3** tube sets (range **1–18**), average age hearing loss first suspected **38 months** (range **0–480**), and mean age of first words **26 months** (range **11–72**). | Registry | Brennan 2024 *JSLHR* |  | https://doi.org/10.1044/2023_JSLHR-23-00179 | (pqac-00000015) |
| Registry findings | Age-group analyses showed significant associations between age group and hearing loss (**p=.019**), otitis media (**p=.001**), and PE tube history (**p=.001**). | Registry | Brennan 2024 *JSLHR* |  | https://doi.org/10.1044/2023_JSLHR-23-00179 | (pqac-00000015) |
| Sleep-circadian mechanism | Sleep disturbance is a hallmark with excessive daytime sleepiness and nighttime agitation, underpinned by **inversion of the melatonin secretion cycle**. | Review | Poisson 2015 *Orphanet Journal of Rare Diseases* |  | https://doi.org/10.1186/s13023-015-0330-x | (pqac-00000006) |
| Sleep-circadian mechanism | The sleep phenotype is reported to result in **>90% of cases** from an **inverted circadian rhythm of melatonin**; inversion was observed in both **RAI1-mutated** patients and those with the **common SMS deletion**. | Mechanistic review | Sciarrillo 2018 thesis/text |  | https://doi.org/10.13130/sciarrillo-maria_phd2018-02-19 | (pqac-00000001) |
| Sleep-circadian mechanism | A 2024 study notes altered melatonin timing with an abnormal inverted circadian rhythm estimated in **95%** of SMS individuals. | Human genomics study/reviewed background | Smieszek 2024 *Egyptian Journal of Medical Human Genetics* |  | https://doi.org/10.1186/s43042-024-00508-3 | (pqac-00000005) |
| Treatments & trials | Combined **morning beta-blocker** and **evening melatonin** may “radically alleviate” circadian rhythm problems in SMS. | Review | Poisson 2015 *Orphanet Journal of Rare Diseases* |  | https://doi.org/10.1186/s13023-015-0330-x | (pqac-00000006) |
| Treatments & trials | A cited study reported **oral β1-antagonist acenbutolol** suppressed daytime melatonin peaks with subjective behavioral improvement; **combined daytime acenbutolol + evening controlled-release melatonin** also produced subjective behavioral improvement. | Human interventional evidence summarized in review | Sciarrillo 2018 thesis/text |  | https://doi.org/10.13130/sciarrillo-maria_phd2018-02-19 | (pqac-00000001) |
| Treatments & trials | **NCT02231008**: completed Phase **2/3** double-blind randomized two-period crossover of **tasimelteon vs placebo**; **49 participants**, start **Sep 2015**, primary completion **2018-11-19**, study completion **Jan 2022**. Primary endpoint: improvement in sleep parameters over **9 weeks**; results/statistics not posted in the retrieved record. | Clinical trial registry | ClinicalTrials.gov NCT02231008 |  | https://clinicaltrials.gov/study/NCT02231008 | (pqac-00000008) |
| Treatments & trials | **NCT00506259**: Phase **1** randomized crossover of bright light phototherapy and controlled-release melatonin in children with SMS; **23 enrolled**; primary outcome was change in melatonin level, with secondary actigraphy/behavior outcomes; no numerical results available in the retrieved record. | Clinical trial registry | ClinicalTrials.gov NCT00506259 |  | https://clinicaltrials.gov/study/NCT00506259 | (pqac-00000011) |
| Treatments & trials | **NCT00691574**: pilot melatonin + bright-light study, non-randomized parallel design; actual enrollment **5**, started **1998-09**, completed **2009-05**; terminated due to funding/extension issues, with no posted efficacy statistics in the retrieved record. | Clinical trial registry | ClinicalTrials.gov NCT00691574 |  | https://clinicaltrials.gov/study/NCT00691574 | (pqac-00000010) |
| Treatments & trials | **NCT03492970**: adult SMS melatonin characterization study, single-group, **10 adults**, hourly plasma melatonin over **24 h** plus ~**2 weeks** actimetry; completed **2019-03-30**; no posted numerical results in the retrieved record. | Clinical trial registry | ClinicalTrials.gov NCT03492970 |  | https://clinicaltrials.gov/study/NCT03492970 | (pqac-00000013) |
| Obesity mechanism | SMS obesity is believed partly due to dysfunction of the **proximal MC4R pathway**; RAI1 haploinsufficiency affects feeding, satiety, and fat deposition. Most people with SMS have overweight/obesity, with **80%** having **BMI ≥85th percentile**, and overeating/foraging often appears by adolescence. | Review + interventional study background | Lazareva 2024 *Obesity Research & Clinical Practice* |  | https://doi.org/10.1016/j.orcp.2024.07.001 | (pqac-00000000) |
| Obesity mechanism | Mouse/mechanistic data summarized in Lazareva 2024: **Rai1+/−** mice show high circulating **leptin** and **PYY**, reduced hypothalamic satiety signaling, reduced **Bdnf**, and reduced **Pomc** expression, supporting upstream dysregulation of melanocortin satiety circuits. | Model/preclinical evidence summarized in human study | Lazareva 2024 *Obesity Research & Clinical Practice*; Javed 2022 *Human Molecular Genetics* |  | https://doi.org/10.1016/j.orcp.2024.07.001 ; https://doi.org/10.1093/hmg/ddab245 | (pqac-00000003, pqac-00000000) |
| Treatments & trials | Open-label phase 2 **setmelanotide** pilot in SMS: **12 enrolled** (ages **11–39**), **10 completed**; once-daily dosing titrated to **3 mg**. Mean percent weight change was **−0.28%** (95% CI **−2.1% to 1.5%**; **P=0.66**), so no significant weight reduction. | Interventional trial | Lazareva 2024 *Obesity Research & Clinical Practice* |  | https://doi.org/10.1016/j.orcp.2024.07.001 | (pqac-00000000) |
| Treatments & trials | In the same setmelanotide SMS pilot, self-reported hunger decreased (**p=0.011**); all participants had adverse events, most commonly injection-site reactions and skin hyperpigmentation, with **no withdrawals or deaths** due to adverse events. | Interventional trial | Lazareva 2024 *Obesity Research & Clinical Practice* |  | https://doi.org/10.1016/j.orcp.2024.07.001 | (pqac-00000000) |
| Genetics/ASD overlap | In a 2024 WGS ASD cohort analysis, **RAI1** rare missense variants were enriched in ASD (**54/6080 ASD** vs **6/2541 controls**, **p<0.002**, OR **3.78**), supporting overlap between SMS-related circadian phenotypes and ASD. | Human genomics study | Smieszek 2024 *Egyptian Journal of Medical Human Genetics* |  | https://doi.org/10.1186/s43042-024-00508-3 | (pqac-00000005) |
| Diagnostics | Recommended testing summarized across cohort/review sources: peripheral blood **FISH**, **CGH array/aCGH**, and **MLPA** for 17p11.2 deletion detection; if negative despite clinical suspicion, proceed to **RAI1 sequencing**. | Review/human cohort | Poisson 2015 *Orphanet Journal of Rare Diseases*; Gouard 2021 *Clinical Genetics* |  | https://doi.org/10.1186/s13023-015-0330-x ; https://doi.org/10.1111/cge.13906 | (pqac-00000006, pqac-00000004) |


*Table: This table compiles the most decision-relevant, quantitatively supported findings on Smith–Magenis syndrome from the retrieved cohort studies, registry analyses, reviews, mechanistic summaries, and clinical trial records. It is useful as a high-yield evidence map for genetics, phenotypes, sleep-circadian biology, obesity, diagnostics, and treatment development.*