Detection ofDeletions andCryptic Translocations in Miller-Dieker SyndromebyInSituHybridization

Summary Fluorescence insitu hybridization (FISH) using two cosmid probes (41AandP13)fromtheMiller-Dieker syndrome (MDS)critical region in17pl3.3 was performed ina blinded comparison ofthree MDS patients withsubmicroscopic deletions andinfournormal relatives used ascontrols. Thecontrols showed both chromosome 17homologues labeled in85%-95%ofcells, while eachpatient showed only one homologue labeled in75%-80%ofcells. TwoMDS patients withcryptic translocations were also studied. Inone case, a patient andhermother hadthe same der(17) (p+),butthereciprocal product ofthetranslocation could notbeidentified inthemother byG-banding (i.e., itwas a "half-cryptic" translocation). FISHrevealed a 3q;17p translocation. Theother caseinvolved a patientwithapparently normal karyotype. Because a large molecular deletion was found, atranslocation involving twoG-negative telomeres (i.e., a"full-cryptic" translocation) was postulated. FISHstudies on herfather andnormal brother showed an 8q;17p translocation. These studies demonstrate that insitu hybridization isan efficient method fordeletion detection inMillerDieker syndrome. Moreimportant, parental studies byFISHon patients demonstrating molecular deletions andanormal karyotype may identify cryptic translocation events,which cannotbedetected byother molecular genetic strategies. Similar insitu strategies fordeletion detection can bedeveloped forother microdeletion syndromes, such asPrader-Willi/Angelman syndrome orDiGeorge syndrome.