Background: Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviours, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births. Heterozygous frameshift mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions.

Objective: Analysis of four individuals with features consistent with SMS for variations in RAI1, using a polymerase chain reaction and sequencing strategy. None of these patients carry 17p11.2 deletions.

Results: Two patients had small deletions in RAI1 resulting in frameshift and premature truncation of the protein. Missense mutations were identified in the other two. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo, as all parental samples were normal. Several polymorphisms were also observed, including new and reported SNPs. The patients’ clinical features differed from those found in 17p11.2 deletion by general absence of short stature and lack of visceral anomalies. All four patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioural anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in one patient of the cohort.

Conclusions: Haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms.