Correspondence

Deletion and Uniparental Disomy Involving the Same Maternal Chromosome 15

N Engl J Med 1994; 330:572-573February 24, 1994

Article

To the Editor:

Genomic imprinting on chromosome 15q11q13 results in two disparate syndromes: Prader-Willi syndrome, in which the paternal 15q11q13 is lacking, and Angelman syndrome, in which the maternal 15q11q13 is lacking1. Loss of a parental region may be due to either physical deletion or uniparental disomy. Uniparental disomy arises when both copies (alleles) of a gene or chromosome are inherited from the same parent, which can result in either identical alleles (isodisomy) or different alleles (heterodisomy)2,3.

We report an unusual case of two different abnormalities of chromosome 15 in one nuclear family. This case highlights the need for timely, careful interpretation of both abnormal and normal fetal karyotypes.

A 38-year-old woman (gravida 4, para 1, abortus 2) underwent prenatal diagnosis because of her advanced age. One previous pregnancy had ended in miscarriage, and another was terminated after a second-trimester amniocentesis (performed because of parental anxiety) showed a proximal 15q deletion. Both parents had normal karyotypes. Chorionic-villus sampling during the most recent pregnancy revealed trisomy 15 in 7 of 27 cells. Since confined placental mosaicism can occur in 2 percent of chorionic-villus samples,4 amniocentesis was performed. A normal karyotype was found in 25 independent colonies.

Because of the possibility of uniparental disomy5,6 and the observation that chromosome 15 was involved in two previous pregnancies, we conducted molecular analyses of chromosome 15q with five DNA probes and four highly polymorphic (CA)_n markers7. One marker, GABRB3 (Figure 1Figure 1Family Tree with an Example of One Molecular Study of Chromosome 15q11q13.), showed two maternal alleles and a faint paternal allele in the villus sample, a finding consistent with mosaic trisomy 15. However, amniocytes contained only the two maternal alleles, indicating nondisjunction at meiosis I (maternal heterodisomy). Thus, the last fetus was at risk for the Prader-Willi syndrome, and the parents elected to terminate the pregnancy. Follow-up molecular studies of genomic DNA from fetal heart and lung tissue confirmed the presence of maternal heterodisomy of chromosome 15 in multiple tissues, with no evidence of mosaic trisomy 15.

Fibroblasts from the first fetus were available. Molecular studies confirmed the 15q deletion from locus D15S13 to locus GABRB3 on the maternal chromosome. Data have suggested that the Prader-Willi syndrome and Angelman syndrome have separate genetic loci7. However, without cloning of the specific gene responsible for Angelman syndrome, it can only be inferred that maternal deletion of proximal 15q put the first fetus at risk for this disorder.

Confined placental mosaicism on chorionic-villus sampling is generally recognized. However, it is less well recognized that a “normal” karyotype on follow-up amniocentesis may not be normal. It seems highly coincidental that two different abnormalities in successive pregnancies involved the same maternal chromosome 15. We postulate an underlying structural defect of this chromosome. An inversion in 15q11q13 could account for both the 15q deletion due to unequal crossing-over in the first fetus and the nondisjunction due to interference with meiotic pairing in the last fetus. With the use of fluorescence in situ hybridization, it may be possible to identify the structural rearrangements.

Linda C. Surh, M.D., Ph.D.
Hungshu Wang, Ph.D.
Alasdair G.W. Hunter, M.D.
Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada

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Citing Articles (6)

Citing Articles

1. 1

   Adrianne Ralph, Fergus Scott, Catherine Tiernan, Madeleine Caubere, Samantha Kollegger, Joan Junio, Cynthia Roberts, Kelly Ewen, Howard R. Slater. (1999) Maternal uniparental isodisomy for chromosome 14 detected prenatally. Prenatal Diagnosis 19:7, 681-684
   CrossRef

2. 2

   Jean-Paul Harpey, Delphine Heron, Muriel Prudent, Sylvie Lesourd, Isabelle Henry, Ghislaine Royer-Legrain, Arnold Munnich, Jean-Paul Bonnefont. (1998) Recurrent meiotic nondisjunction of maternal chromosome 15 in a sibship. American Journal of Medical Genetics 76:1, 103-104
   CrossRef

3. 3

   Eileen Roberts, K. Stevenson, T. Cole, D. H. A. Redford, E. V. Davison. (1997) Prospective Prenatal Diagnosis of Prader–Willi Syndrome due to Maternal Disomy for Chromosome 15 following Trisomic Zygote Rescue. Prenatal Diagnosis 17:8, 780-783
   CrossRef

4. 4

   Kelly J. Connerton-Moyer, Robert D. Nicholls, Stuart Schwartz, Daniel J. Driscoll, Jill E. Hendrickson, Charles A. Williams, Richard M. Pauli. (1997) Unexpected familial recurrence in Angelman syndrome. American Journal of Medical Genetics 70:3, 253-260
   CrossRef

5. 5

   HOWARD R. SLATER, CATHRYN VAUX, MARK PERTILE, TRENT BURGESS, VIDA PETROVIC. (1997) PRENATAL DIAGNOSIS OF PRADER–WILLI SYNDROME USING PW71 METHYLATION ANALYSIS—UNIPARENTAL DISOMY AND THE SIGNIFICANCE OF RESIDUAL TRISOMY 15. Prenatal Diagnosis 17:2, 109-113
   CrossRef

6. 6

   SUSAN L. CHRISTIAN, ANN C. M. SMITH, MICHELLE MACHA, SUSAN H. BLACK, FREDERICK F. B. ELDER, JAMIE M.-P. JOHNSON, ROBERT G. RESTA, URVASHI SURTI, LORRAINE SUSLAK, MARION S. VERP, DAVID H. LEDBETTER. (1996) PRENATAL DIAGNOSIS OF UNIPARENTAL DISOMY 15 FOLLOWING TRISOMY 15 MOSAICISM. Prenatal Diagnosis 16:4, 323-332
   CrossRef