Linkage analysis withchromosome 15qll-13 markers showsgenomic imprinting infamilial Angelman syndrome

Angelmansyndrome(AS)andPraderWillisyndrome(PWS)havebecomethe classical examplesofgenomicimprintinginman,ascompletely different phenotypesaregenerated by theabsence ofmaternal(AS)or paternal (PWS) contributions to theqll-13regionof chromosome15asaresult ofdeletion or uniparental disomy.Apparently, most patients aresporadic cases. Thegenetic mechanismunderlying familial AS has remainedenigmatic fora longtime. Recently, evidencehasbeenemerging suggesting autosomal dominantinheritanceofadetectable orundetectable defectinageneorgenesat15ql1-13, subject togenomicimprinting. Thepresent reportdescribes anunusually largepedigreewithsegregation ofAS through maternalinheritance and apparent asymptomatictransmissionthrough severalmale ancestors. Deletionand paternaldisomy at 15ql1-13were excluded. However,thegenetic defect is still located inthisregion, asweobtained amaximum lodscoreof540forlinkage totheGABA receptor locusGABRB3 and theanonymousDNA markerDISSlO, whichhavebeenmappedwithin oradjacenttotheAS critical region at15qll-13. Thesizeofthepedigree allowed calculationofanoddsratio infavourofgenomic imprinting of925x105. Thisfamilyillustrates thenecessity ofextensive pedigree analysis when considering recurrence risksforrelatives ofAS patients, those withoutdetectable deletion ordisomyin particular.MedGenet1993;30:853-7)