Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum.
OBJECTIVE
Smith-Magenis syndrome (SMS) is a complex disorder that includes mental retardation, craniofacial and skeletal anomalies, and behavioral abnormalities. We report the molecular and genotype-phenotype analyses of 31 patients with SMS who carry 17p11.2 deletions or mutations in the RAI1 gene.


METHODS
Patients with SMS were evaluated by fluorescence in situ hybridization and/or sequencing of RAI1 to identify 17p11.2 deletions or intragenic mutations, respectively, and were compared for 30 characteristic features of this disorder by the Fisher exact test.


RESULTS
In our cohort, 8 of 31 individuals carried a common 3.5 Mb deletion, whereas 10 of 31 individuals carried smaller deletions, two individuals carried larger deletions, and one individual carried an atypical 17p11.2 deletion. Ten patients with nondeletion harbored a heterozygous mutation in RAI1. Phenotypic comparison between patients with deletions and patients with RAI1 mutations show that 21 of 30 SMS features are the result of haploinsufficiency of RAI1, whereas cardiac anomalies, speech and motor delay, hypotonia, short stature, and hearing loss are associated with 17p11.2 deletions rather than RAI1 mutations (P<.05). Further, patients with smaller deletions show features similar to those with RAI1 mutations.


CONCLUSIONS
Although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome.
Girirajan
Santhosh
S
Department of Human Genetics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Vlangos
Christopher N
CN
Szomju
Barbara B
BB
Edelman
Emily
E
Trevors
Christopher D
CD
Dupuis
Lucie
L
Nezarati
Marjan
M
Bunyan
David J
DJ
Elsea
Sarah H
SH
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D013577:Syndrome; D015534:Trans-Activators; D014157:Transcription Factors
D011506:Proteins; C431552:RAI1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors