Annette E. Cockwell

Maternal uniparental disomy for chromosome 14.

We report the first case of maternal uniparental disomy of chromosome 14 in humans. The male proband inherited a balanced 13;14 Robertsonian translocation from his mother. Molecular studies showed that neither chromosome 14 was of paternal origin. The proband is of above average intelligence, but he has hydrocephalus, a bifid uvula, premature puberty, short stature, and small testes. It is not known if the clinical findings are related or coincidental to the uniparental disomy.

A cytogenetic and molecular reappraisal of a series of patients with Turner's syndrome.

The results of a cytogenetic and molecular reinvestigation of a series of 52 patients with Turners syndrome are reported. No evidence of Y chromosome material was found among the patients with a 45, X constitution but two patients were found to have a cell line with a r(Y) chromosome which was previously thought to be a r(X). The parental origin of the single X in the 45, X patients was maternal in 69% and paternal in 31%, a similar ratio to that seen among spontaneously aborted 45, X conceptuses. This suggests that X‐chromosome imprinting is not responsible for the two grossly different phenotypes associated with a 45, X chromosome constitution. Approximately half of the structurally abnormal X chromosomes were maternal in origin and half paternal. This observation is consistent with either a meiotic or post‐zygotic mitotic origin and at variance with the predominantly paternal origin reported for autosome structural abnormalities.

A cytogenetic and molecular study of a series of 45,X fetuses and their parents.

The parental origin of the single X chromosome in 10 45,X fetuses was studied using DNA restriction fragment length polymorphisms. In six the single X was maternal in origin, in one it was paternal, and in one the results were consistent with a paternal origin. Therefore the parental origin of the X in 45,X fetuses that survive to the second or third trimester of pregnancy is similar to that of spontaneous abortions and live births with a 45,X constitution. The mothers of two of the fetuses were themselves found to have an abnormal sex chromosome complement, but in neither case did it appear to be related to the chromosome abnormality in the fetus.

Three patients with ring (X) chromosomes and a severe phenotype.

Three patients with mosaicism and a cell line containing a small ring (X) chromosome are described. Their phenotype is similar to several previously reported patients with a 45,X/46,X,r(X) karyotype and a phenotype far more severely affected than expected in Turners syndrome. The clinical picture includes mental retardation, a facial appearance reminiscent of the Kabuki make up syndrome, and limb anomalies. Some of the patients also had streaky hyperpigmentation of the skin in a pattern suggesting dermal mosaicism. It has been hypothesised that the severe phenotype might be the result of the small r(X) chromosome remaining active. However, there is little critical evidence to support this suggestion, while there is considerable evidence against it, including (1) a similar phenotype in 45,X/46,X,r(Y) patients, (2) the late replication of some of the small r(X) chromosomes associated with this phenotype, and (3) the expression of XIST in some of the affected patients.

Centromeric inactivation in a dicentric human Y;21 translocation chromosome

Abstract. A de novo dicentric Y;21 (q11.23;p11) translocation chromosome with one of its two centromeres inactive has provided the opportunity to study the relationship between centromeric inactivation, the organization of alphoid satellite DNA and the distribution of CENP-C. The proband, a male with minor features of Down’s syndrome, had a major cell line with 45 chromosomes including a single copy of the translocation chromosome, and a minor one with 46 chromosomes including two copies of the translocation chromosome and hence effectively trisomic for the long arm of chromosome 21. Centromeric activity as defined by the primary constriction was variable: in most cells with a single copy of the Y;21 chromosome, the Y centromere was inactive. In the cells with two copies, one copy had an active Y centromere (chromosome 21 centromere inactive) and the other had an inactive Y centromere (chromosome 21 centromere active). Three different partial deletions of the Y alphoid array were found in skin fibroblasts and one of these was also present in blood. Clones of single cell origin from fibroblast cultures were analysed both for their primary constriction and to characterise their alphoid array. The results indicate that (1) each clone showed a fixed pattern of centromeric activity; (2) the alphoid array size was stable within a clone; and (3) inactivation of the Y centromere was associated with both full-sized and deleted alphoid arrays. Selected clones were analysed with antibodies to CENP-C, and staining was undetectable at both intact and deleted arrays of the inactive Y centromeres. Thus centromeric inactivation appears to be largely an epigenetic event.

X inactivation analysis in a female with hypomelanosis of Ito associated with a balanced X;17 translocation: evidence for functional disomy of Xp.

X inactivation analysis was performed on normal and hypopigmented skin samples obtained from a female with hypomelanosis of Ito associated with a balanced whole arm X;17 translocation. Severe skewing of X inactivation resulting in inactivity of the intact X was found in blood and cultures of both types of skin, but analysis of DNA prepared directly from hypopigmented skin showed significant inactivation of the translocated X, inconsistent with the usual mechanism of phenotypic expression in X;autosome translocations. In addition, dual colour FISH analysis using centromere specific probes for chromosomes X and 17 showed that the breakpoints on both chromosomes lie within the alphoid arrays, making interruption of a locus on either chromosome unlikely. While partial variable monosomy of loci on chromosome 17p cannot be excluded as contributing to the phenotype in this patient, it is argued that the major likely factor is partial functional disomy of sequences on Xp in cell lineages that have failed to inactivate the intact X chromosome.

A CASE OF MATERNAL UNIPARENTAL DISOMY OF CHROMOSOME 9 IN ASSOCIATION WITH CONFINED PLACENTAL MOSAICISM FOR TRISOMY 9

We describe the first case of maternal uniparental disomy (UPD) of chromosome 9 in a fetus who was shown to have mosaic trisomy 9 in a chorionic villus sample. Karyotyping and molecular studies following termination of the pregnancy confirmed mosaicism in the placenta and maternal UPD(9) in the fetal tissues. This case demonstrates that the mechanism of trisomy correction may result in a fetus with UPD(9).

The origin of trisomy 13

Trisomy 13 is one of the most common trisomies in clinically recognized pregnancies and one of the few trisomies identified in liveborns, yet relatively little is known about the errors that lead to trisomy 13. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 78 cases of trisomy 13. Our results indicate that the majority of cases (>91%) are maternal in origin and, similar to other autosomal trisomies, the extra chromosome is typically due to errors in meiosis I. Surprisingly, however, a large number of errors also occur during maternal meiosis II (∼37%), distinguishing trisomy 13 from other acrocentric and most nonacrocentric chromosomes. As with other trisomies, failure to recombine is an important contributor to nondisjunction of chromosome 13.

Germline and somatic mosaicism in a female carrier of Duchenne muscular dystrophy.

The family of a male with Duchenne muscular dystrophy (DMD) and a deletion within the dystrophin gene has been studied. Polymerase chain reaction analysis of ectopic mRNA from peripheral blood T+B lymphocytes and the use of (CA)n repeat polymorphisms in and around the deleted region showed the probands mother to be both a germline mosaic and a somatic mosaic for the deletion seen in her son. The mutation therefore occurred as a mitotic event early in embryogenesis.

Is karyotyping couples experiencing recurrent miscarriage worth the cost

Please cite this paper as: Barber J, Cockwell A, Grant E, Williams S, Dunn R, Ogilvie C. Is karyotyping couples experiencing recurrent miscarriage worth the cost? BJOG 2010;117:885–888.