Research Letter Angelman Syndrome Caused by an Identical Familial 1,487-kb Deletion

To the Editor:Angelman syndrome (AS, OMIM #105830) is aneurodevelopmentaldisordercharacterizedbymen-tal retardation, ataxia, hypotonia, epilepsy, absenceof speech, and specific facial features. At least fourmajor mechanisms causing AS were validated: (i)an interstitial deletion of 15q11-q13 (70–75%), (ii)uniparental disomy (2–3%), (iii) imprinting defects(3–5%),(iv)UBE3A mutations(20%)[Clayton-Smithand Laan, 2003]. Most deletions are similar in size(approximate 4 Mb) and occur de novo throughmaternal unequal crossing over between low copyrepeats (LCRs). Paternal occurrence of similar dele-tions, instead, results in Prader–Willi syndrome(PWS,OMIM#176270).InPWSnocodingmutationshavebeenfoundincontrastwithUBE3AmutationsinAS,suggestingthatPWSiscausedbylossoffunctionof multiple genes.Different sized deletions associated with AS arevery rare. To our knowledge, at least three familialatypical deletions were reported [Saitoh et al., 1992;Buxton et al., 1994; Burger et al., 2002], but in onefamily[Buxtonetal.,1994]amicrodeletioncouldnotbeconfirmedbyanothergroup[Sutcliffeetal.,1997].Intheremainingtwofamilies,microdeletionscausedAS in maternal inheritance but no PWS features inpaternal inheritance, enabling differentiation of thePWS critical region (PWSCR) from the AS criticalregion (ASCR).We encountered a similar family with an atypicalmicrodeletion through microarray CGH analysis of30 individuals with idiopathic mental retardation[Miyake et al., 2006]. The family consisted of a boy,who was later confirmed with AS, and an asympto-maticmotherandmaternalgrandfather(Fig.1A).Allthree had an atypical microdeletion. MethylationPCR analysis [Kubota et al., 1997] of the probandshowed a normal pattern (data not shown).The deletion was intensively analyzed. FISHanalysis using RPCI-11 BAC clones (701H24, 171C8,1081A4,607F22,931B1,2C7,434O21,203C13,638J6,899B22, 58D7, and 142M24) on the proband’smetaphase chromosomes revealed that 1081A4,607F22, 931B1, 2C7, 434O21, 203C13, 638J6,899B22, and 58D7 were deleted, 171C8 and142M24 were partially deleted, and 701H24 was notdeleted (data not shown). Cosmid subclones con-structedfromBAC171C8wereusedforfurtherFISHanalysis. Cosmid D-2 was partially deleted (data notshown),indicatingthattheproximaldeletionbreak-point was located in a region between UCSCcoordinate chromosome 15 nucleotide 22,928,853and 22,974,812 (end sequences of cosmid D-2).Subsequently quantitative real-time PCR (qPCR)