Smith-Magenis (RAI1)/Miller-Dieker Probe Combination
Smith-Magenis syndrome (SMS) is a multiple congenital anomaly syndrome characterised by mental retardation, neurobehavorial abnormalities, sleep disturbances, short stature, minor craniofacial and skeletal anomalies, congenital heart defects and renal anomalies1,2.
It is one of the most frequently observed human microdeletion syndromes and is associated with an interstitial deletion of the chromosome band 17p11.22.
Molecular studies in SMS patients suggest a minimally deleted region (MDR) spanning approximately 700kb3,5, though the common deletion is around 4Mb in size4. The proximal boundary of the MDR is within a region of overlap between the FLII and LLGL1 genes, and the distal boundary within the PEMT gene3. Deletions or mutations in RAI1 (Retinoic Acid Induced 1) gene, which lies within the MDR, are associated with the syndrome3,5,6,7. RAI1 was shown to be the primary gene responsible for most features of SMS8,9.
Whilst deletion of the 17p11.2 region results in SMS, duplication of the same region results in a similar, yet distinct, disorder known as Potocki-Lupski syndrome10. Phenotypically this shares many similarities to SMS, though it is generally milder, but does have some unique clinical findings10.
The common duplication involves the same 4Mb region as the SMS deletion as both syndromes are mediated by non-allelic homologous recombination between flanking low copy repeat regions4.
Miller-Dieker syndrome (MDS) is a multiple malformation characterized by classical lissencephaly, a characteristic facial appearance andsometimes other birth defects11. It is associated with visible or submicroscopic rearrangements within chromosome band 17p13.3 in almost all cases12. Isolated lissencephaly sequence (ILS) consists of classical lissencephaly with no other major anomalies13. Submicroscopic deletions of chromosome 17p13.3 have been detected in almost 40% of these patients12.
MDS is considered a contiguous gene deletion syndrome where deletion of physically contiguous genes leads to the complex phenotypic abnormalities observed. The PAFAH1B1 (LIS1) gene is located at 17p13.3 and is recognised as the causative gene for the lissencephaly phenotype in both MDS and ILS14,15. Deletions in MDS patients always include the PAFAH1B1 gene, together with other telomeric loci to a distance in excess of 250kb14.
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4. Lupski. Nature Genetics 2007; 39:S43 - S47
5. Girirajan S et al., J Med Genet 2005;42:820-8
6. Bi W et al., Am J Med Genet 2006;140(22):2454-63
7. Slager RE et al., Nat Genet 2003;33:466-8
8. Schoumans J et al., Eur J Med Genet 2005;48(3):290-300
9. Girirajan S et al., Genet Med 2006;8(7):417-27
10. Potocki et al., Am J Hum Genet 2007; 80 (4): 633–649
11. Dobyns WB et al., Am J Hum Genet 1991;48:584-94
12. Dobyns WB et al., J Am Med Assoc 1993;270:2838-42
13. Dobyns WB et al., Neurology 1992;42:1375-88
14. Chong SS et al., Hum Mol Genet 1997;6(2):147-55
15. Lo Nigro C et al., Hum Mol Genet 1997;6(2):157-64
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