Chapter 01

What Smith-Magenis Syndrome is

The genetics, the prevalence, and why the published number is probably a floor.

Smith-Magenis Syndrome is a neurodevelopmental condition caused by the loss of one working copy of the RAI1 gene. In roughly 90% of cases that happens through a deletion on chromosome 17 at 17p11.2 which takes RAI1 with it; in the remaining ~10% RAI1 itself carries a pathogenic variant while the chromosome is intact.

It is almost always de novo — it arises in the affected person rather than being inherited. Two consequences follow. Parents did not pass it on, and there is usually no family history to notice, which removes the signal that often prompts genetic testing in other conditions.

How common

Published estimates put it between 1 in 15,000 and 1 in 25,000 births. Treat that as a floor rather than a measurement.

Prevalence figures count diagnosed cases. GeneReviews notes that the true prevalence may be closer to 1 in 15,000, and the 2026 systematic review of neurodevelopmental diagnoses in SMS shows why under-recognition is plausible: autism and ADHD features are common in published SMS cohorts. The denominator is therefore uncertain, and every number derived from it — registry size, trial planning, funding cases — inherits that uncertainty.