MOLECULAR ANALYSES OF 17P11.2 DELETIONS IN 62 SMITH-MAGENIS SYNDROME PATIENTS

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple co ngenital anomalies/mental retardation syndrome caused by an interstiti al deletion involving band p11.2 of chromosome 17. Toward the molecula r definition of the interval. defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected pa rents were molecularly analyzed with respect to the presence or absenc e of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii) PCR and Southern an alysis of somatic cell hybrids retaining the deleted chromosome 17 fro m selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel an onymous markers and a new microsatellite marker was determined in 17p1 1.2. The results confirmed that the proximal deletion breakpoint in th e majority of SMS patients is located between markers D17S58 (EW301) a nd D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal. breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in a ll 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly dis tinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.