Recurrent meiotic nondisjunction of maternal chromosome 15 in a sibship
2
Letter to the Editor Recurrent Meiotic Nondisjunction of Maternal Chromosome 15 in a Sibship To the Editor: Angelman syndrome (AS) and Prader-Willi syn- drome (PWS) are developmental disorders caused by the loss of function of distinct genes mapping close to each other on chromosome 15q11–q13. Due to genomic imprinting, genes involved in AS and PWS are sug- gested to be expressed from the maternal and paternal copies of chromosome 15, respectively [Nicholls, 1994]. Genetic counselling for these conditions depends on their molecular mechanism, which may fall into six classes: (1) structural rearrangements (such as inver- sions or translocations) [Hulten et al., 1991; Smeets et al., 1992], (2) interstitial deletions [Knoll et al., 1989], (3) uniparental disomies (UPD) [Nicholls et al., 1989; Malcolm et al., 1991], (4) imprinting mutations of the 15q11–13 region [Reis et al., 1994], (5) UBE3A gene mutations (specific to AS) [Kishino et al., 1997; Mat- suura et al., 1997], and (6) no detectable molecular ab- normality. While most cases are sporadic, some fami- lies are exposed to a high risk of recurrence, especially when one parent is carrying a balanced translocation [Donnai, 1993], a deletion [Hamabe et al., 1991], an imprinting mutation [Reis et al., 1994], or an UBE3A mutation [Kishino et al., 1997], or when molecular studies are normal. Otherwise, the recurrence risk, specifically that of UPD, is supposed to be very low but not nil, as is illustrated by the following report. The proposita, a girl born to a 26-year-old female and a 36-year-old male, had typical AS. Chromosome and FISH analyses with SNRPN (small nuclear ribonucleo- protein N) and GABR-B3 (GABA A receptor B3 sub- unit) probes (Oncor, Gaithersburg, MD) were normal. The lack of contribution of maternal chromosome 15 to the proposita’s genotype was shown by molecular analysis, using the polymorphic markers of chromo- some 15q, i.e., GABR-B3, D15S153, and D15S120 (Fig. 1). The absence of heterozygosity throughout the entire 15q region was additionally demonstrated by the CA repeat polymorphisms D15S541, D15S118, and D15S126, linked to 15q11, 15q14–15, and 15q21, re- spectively [Malcolm and Donlon, 1994] (data not shown). This was consistent with paternal UPD arising from either a meiosis 2 nondisjunction with no recom- bination, or a postzygotic duplication of chromosome 15 in a monosomic conceptus. High-resolution chromo- some analysis (550 bands) was normal in both parents. The next pregnancy terminated spontaneously at 10 weeks of gestation. Cytogenetic analysis of trophoblast *Correspondence to: Jean-Paul Bonnefont, Service de Bio- chimie B, Tour Lavoisier e ´tage 4, Groupe Hospitalier Necker En- fants Malades, 149, rue de Se ` vres, 75 743 Paris Cedex 15, France. Received 15 September 1997; Accepted 7 November 1997 Fig. 1. Chromosome 15 analysis with CA repeat polymorphic markers. The CA repeat polymorphism GABR-B3 (GABA A receptor B3 subunit) maps within the critical PW/AS region, while two other markers, D15S153 and D15S120, are more telomeric [Malcolm and Donlon, 1994]. DNA was amplified according to standard conditions (annealing temperature 55°C for all primers). Primers sequences are as in Malcolm and Donlon [1994] The resulting products were electrophoresed on a 6% polyacrylamide/7 M urea gel. The gel was blotted onto a nylon membrane, hybridized with a (GT) 10 probe labeled by chemoluminescence according to the manufactur- er’s instructions (ECL direct nucleic acid labeling and detection systems, Amersham Life Science, Buckinghamshire, UK), and exposed to X-ray film for 10 min. Arrows indicate the 15q alleles from either the trisomic tro- phoblast (right) or the AS proposita (left). It is worth noting that both concepti have inherited the same paternal allele at GABR-B 3 and the D15S120 loci, while their paternal alleles are distinct at the D15S153 locus, due to a recombination event. American Journal of Medical Genetics 76:103–104 (1998) © 1998 Wiley-Liss, Inc.
Transcript of Recurrent meiotic nondisjunction of maternal chromosome 15 in a sibship
Letter to the Editor
Recurrent Meiotic Nondisjunction of MaternalChromosome 15 in a Sibship
To the Editor:
Angelman syndrome (AS) and Prader-Willi syn-drome (PWS) are developmental disorders caused bythe loss of function of distinct genes mapping close toeach other on chromosome 15q11–q13. Due to genomicimprinting, genes involved in AS and PWS are sug-gested to be expressed from the maternal and paternalcopies of chromosome 15, respectively [Nicholls, 1994].Genetic counselling for these conditions depends ontheir molecular mechanism, which may fall into sixclasses: (1) structural rearrangements (such as inver-sions or translocations) [Hulten et al., 1991; Smeets etal., 1992], (2) interstitial deletions [Knoll et al., 1989],(3) uniparental disomies (UPD) [Nicholls et al., 1989;Malcolm et al., 1991], (4) imprinting mutations of the15q11–13 region [Reis et al., 1994], (5) UBE3A genemutations (specific to AS) [Kishino et al., 1997; Mat-suura et al., 1997], and (6) no detectable molecular ab-normality. While most cases are sporadic, some fami-lies are exposed to a high risk of recurrence, especiallywhen one parent is carrying a balanced translocation[Donnai, 1993], a deletion [Hamabe et al., 1991], animprinting mutation [Reis et al., 1994], or an UBE3Amutation [Kishino et al., 1997], or when molecularstudies are normal. Otherwise, the recurrence risk,specifically that of UPD, is supposed to be very low butnot nil, as is illustrated by the following report.
The proposita, a girl born to a 26-year-old female anda 36-year-old male, had typical AS. Chromosome andFISH analyses with SNRPN (small nuclear ribonucleo-protein N) and GABR-B3 (GABA A receptor B3 sub-unit) probes (Oncor, Gaithersburg, MD) were normal.The lack of contribution of maternal chromosome 15 tothe proposita’s genotype was shown by molecularanalysis, using the polymorphic markers of chromo-some 15q, i.e., GABR-B3, D15S153, and D15S120(Fig. 1).
The absence of heterozygosity throughout the entire15q region was additionally demonstrated by the CArepeat polymorphisms D15S541, D15S118, andD15S126, linked to 15q11, 15q14–15, and 15q21, re-
spectively [Malcolm and Donlon, 1994] (data notshown). This was consistent with paternal UPD arisingfrom either a meiosis 2 nondisjunction with no recom-bination, or a postzygotic duplication of chromosome 15in a monosomic conceptus. High-resolution chromo-some analysis (550 bands) was normal in both parents.
The next pregnancy terminated spontaneously at 10weeks of gestation. Cytogenetic analysis of trophoblast
*Correspondence to: Jean-Paul Bonnefont, Service de Bio-chimie B, Tour Lavoisier etage 4, Groupe Hospitalier Necker En-fants Malades, 149, rue de Sevres, 75 743 Paris Cedex 15, France.
Received 15 September 1997; Accepted 7 November 1997
Fig. 1. Chromosome 15 analysis with CA repeat polymorphic markers.The CA repeat polymorphism GABR-B3 (GABA A receptor B3 subunit)maps within the critical PW/AS region, while two other markers, D15S153and D15S120, are more telomeric [Malcolm and Donlon, 1994]. DNA wasamplified according to standard conditions (annealing temperature 55°Cfor all primers). Primers sequences are as in Malcolm and Donlon [1994]The resulting products were electrophoresed on a 6% polyacrylamide/7 Murea gel. The gel was blotted onto a nylon membrane, hybridized with a(GT)10 probe labeled by chemoluminescence according to the manufactur-er’s instructions (ECL direct nucleic acid labeling and detection systems,Amersham Life Science, Buckinghamshire, UK), and exposed to X-ray filmfor 10 min. Arrows indicate the 15q alleles from either the trisomic tro-phoblast (right) or the AS proposita (left). It is worth noting that bothconcepti have inherited the same paternal allele at GABR-B3 and theD15S120 loci, while their paternal alleles are distinct at the D15S153locus, due to a recombination event.
American Journal of Medical Genetics 76:103–104 (1998)
© 1998 Wiley-Liss, Inc.
cells (embryonic tissues could not be recovered) wasperformed due to the occurrence of AS in the previousoffspring, and showed a nonmosaic trisomy 15. A studywith microsatellite markers covering the entire 15q re-gion detected the presence of one paternal allele andtwo distinct maternal alleles (Fig. 1), suggesting ameiosis 1 nondisjunction event in the maternal gamete.
This report emphasizes the possibility of recurrentmaternal meiosis 1 nondisjunction, apart from the con-text of advanced maternal age. In this case, one canpostulate the presence of a ‘‘maternal’’ factor, alterna-tively resulting in reciprocal events of either nullisomyor disomy for chromosome 15 in the egg. Fertilization ofa nullisomic egg by a normal sperm would result inmonosomy 15, a lethal condition, unless further dupli-cation of the paternal counterpart ‘‘rescues’’ the preg-nancy, thus resulting in AS with complete paternal iso-disomy (first pregnancy). Fertilization of a disomic eggby a normal sperm would result in trisomy 15, leadingto a miscarriage (second pregnancy), unless trisomy iscorrected by the loss of either the paternal (maternalheterodisomy) or one maternal chromosome 15, result-ing either in PWS or in a normal conceptus, respec-tively. Such recurrent events of meiotic nondisjunctioncould arise from a structural defect in a chromosome15, such as a cryptic inversion, interfering with meioticpairing. This hypothesis has recently been raised inconnection with the occurrence of two different abnor-malities (UPD and deletion) of a maternal chromosome15 in one nuclear family [Surh et al., 1994]. Since suchcryptic rearrangements usually escape detection by cy-togenetics tools, genetic counselling should take intoaccount that the recurrence risk, although low, is notnil in AS or PWS resulting from UPD.
REFERENCESDonnai D (1993): Robertsonian translocations: Clues to imprinting. Am J
Med Genet 46:681–682.
Hamabe J, Kuroki Y, Imaizumi K, Sugimoto T, Fukushima Y, YamaguchiA, Izumikawa Y, Niikawa N (1991): DNA deletion and its parentalorigin in Angelman syndrome patients. Am J Med Genet 41:64–68.
Hulten M, Armstrong S, Challinor P, Gould C, Hardy G, Leedham P, LeeT, McKeown C (1991): Genomic imprinting in an Angelman andPrader-Willi translocation family. Lancet 338:638–639.
Kishino T, Lalande M, Wagstaff J (1997): UBE3A/E6-AP mutations causeAngelman syndrome. Nat Genet 15:70–73.
Knoll JHM, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA(1989): Angelman and Prader-Willi syndromes share a common chro-mosome 15 deletion but differ in parental origin of the deletion. Am JMed Genet 32:285–90.
Malcolm S, Donlon TA (1994): Report on the Second International Work-
shop on Human Chromosome 15 Mapping 1994. Cytogenet Cell Genet67:2–14.
Malcolm S, Clayton-Smith J, Nichols M, Robb S, Webb T, Armour JAL,Jeffreys AJ, Pembrey ME (1991): Uniparental paternal disomy in An-gelman’s syndrome. Lancet 337:694–697.
Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS,Rommens JM, Beaudet AL (1997): De novo truncating mutations inE6-AP ubiquitin protein ligase gene (UBE3A) in Angelman syndrome.Nat Genet 15:74–77.
Nicholls RD (1994): New insights reveal complex mechanisms involved ingenomic imprinting. Am J Hum Genet 54:733–740.
Nicholls RD, Knoll JHM, Butler MG, Karam S, Lalande M (1989): Geneticimprinting suggested by maternal heterodisomy in non-deletionPrader-Willi syndrome. Nature 342:281–285.
Reis A, Dittrich B, Greger V, Buiting K, Lalande M, Gillessen-Kaesbach,Anvret M, Horsthemke B (1994): Imprinting mutations suggested byabnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet 54:741–747.
Smeets DFCM, Hamel BCJ, Smeets HJM, Bollen JHM, Smits APT, RopersHH, Van Oost BA (1992): Prader-Willi syndrome and Angelman syn-drome in cousins from a family with a translocation between chromo-somes 6 and 15. N Engl J Med 326:807–811.
Surh LC, Wang H, Hunter AGW (1994): Deletion and uniparental disomyinvolving the same maternal chromosome 15. N Engl J Med 330:572–573.
Jean-Paul HarpeyDelphine HeronMuriel PrudentSylvie LesourdService de Pediatrie GenetiqueGroupe Hospitalier Pitie SalpetriereParis, France
Isabelle HenryUnite INSERM U 383Groupe HospitalierNecker Enfants MaladesParis, France
Ghislaine Royer-LegrainArnold MunnichService de Genetique MedicaleGroupe HospitalierNecker Enfants MaladesParis, France
Jean-Paul Bonnefont*Service de Biochimie GenetiqueGroupe HospitalierNecker Enfants MaladesParis, Fance
104 Harpey et al.
