Maternal uniparental isodisomy of human chromosome 14 associated with a paternal t(13q14q) and precocious puberty.

Cytogenetic and molecular investigation of a boy with precocious puberty and motor developmental delay revealed a 45,XY,t(14q14q) or i(14q) karyotype with no paternal chromosome 14 contribution. VNTR analysis of loci on four other chromosomes excluded non-paternity with greater than 99% confidence. Results of VNTR and CA repeat analyses of ten loci along the entire length of chromosome 14 were consistent with homozygosity at all loci, suggesting that the chromosomal rearrangement was a maternal isochromosome for 14q. As the proband's father had a balanced Robertsonian translocation, t(13q14q), we suggest that the origin of the maternal uniparental disomy (UPD) was fertilization by a nullisomy 14 sperm with formation of the isochromosome in the early embryo. Also, the proband has several clinical features in common with six previously reported liveborn cases of maternal UPD 14: hypotonia and motor developmental delay, mild dysmorphic facial features, low birth weight and growth abnormalities, and, more specifically, precocious puberty among the four cases old enough to assess. The emergence of a syndrome associated with maternal UPD 14 suggests the possibility of genomic imprinting of regions of chromosome 14, especially a gene involved in the onset of puberty.

Trisomy 21 Down syndrome. II. Structural chromosome rearrangements in the parents.

In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased ascertainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of etiologic significance.

The fragile X in cattle.

In search of an animal model for the human fragile X syndrome, the chromosomes of Holstein cows were examined. This breed was chosen because of previous studies on the baldy calf syndrome. An achromatic gap was observed at a specific site on the X chromosome closer to the centromere than that identified in humans. This unstained gap was found in 3%-4% of cells of the following four animals: an affected calf, her sister, their mother, and an unrelated Holstein cow. The bovine fragile X may not be analogous to the human fragile X but its location may be important as a genetic marker in linkage studies involving the loci for hypoxanthine phosphoribosyltransferase (HPRT) and glucose-6-phosphate dehydrogenase (G-6-PD).

Detection and interpretation of two different cell lines in triploid abortions.

Among a series of 98 triploid abortions, there were four specimens with two cells lines. The detection of two clones was by Q-banding of chromosomes. Two of these four specimens were dizygotic twins, the third was either a mosaic or monozygotic twins with loss of a sex chromosome from one twin and the fourth was best explained as a chimaera which arose by fertilization of two female pronuclei by three sperms. These two unusual specimens had XYY sex chromosome complements which is rare among triploids. Two additional specimens were diagnosed clinically as possible twin pregnancies but only one cell line was identified from tissue culture. The frequency of twins was of the order of 1/33.

Triploidy and chromosomes.

In a total sample of 105 triploid spontaneous abortions and live-born and stillborn infants, the parental origin could be determined in 77%. Dispermy was the most common cause of this abnormality. Among the digynic triploids 69% resulted from retention of the second polar body. Parental ages did not differ from those of the general population except for 10 aneuploid triploids with significantly elevated parental ages. In five sibships, simple aneuploidy in another pregnancy was observed, four of them being potentially viable. Two sisters had triploid conceptions. There were four twin pregnancies, a frequency of one in 26. Only two triploids had an XYY sex chromosome complement, one of which was mosaic with loss of an autosome and the other was a chimera. A frequency of almost 50% of mothers exposed to preconception abdominal radiation is suggestive of an association between radiation and triploidy and requires further investigation.

Trisomy 21 Down syndrome. Parental mosaicism.

The lymphocyte chromosomes of trisomy 21 Down syndrome patients and their parents in a random series of 374 families were analyzed, the objective being the identification of parental mosaicism. The numbers of parents in whom at least two trisomy 21 cells were detected were seven mothers and three fathers, a frequency of 2.7% of families. Confirmation of mosaicism was by identification of parental transmission of the extra chromosome to the progeny, by repeat chromosome analysis, and/or by the presence of more than one affected child. If to these are added six others in whom only one trisomic cell was detected, but with no other supporting evidence, the frequency could be as high as 4.3%. Differences in parental age at the birth of Down syndrome progeny may be accounted for by differences in frequencies of mosaicism in germ cells and somatic tissue. Mosaicism was found more frequently in the mothers than in the fathers, but more data are required for confirmation of a real difference.

Additional evidence for fragile X activity in heterozygous carriers.

The result of a previous study showing an association between mental development and fragile X activity in heterozygous females is given further support by similar investigations of three additional kindreds. The increased frequency of demonstrable fragile X chromosomes in mentally retarded females appears to be due to an increase in the active fragile X while the inactive marker X remains at a similar low frequency in all heterozygotes whether retarded or not. The frequencies of the active fragile X separated the normal and abnormal subjects into two distinct populations. The suggested inverse correlation between the number of lymphocytes with detectable fragile X chromosomes and advancing age can be attributed to ascertainment biases.

Twinning rate in spontaneous abortions.

An unselected series of spontaneous abortions and their mothers were karyotyped with Q-bands to obtain a frequency of twin conceptions lost during the first trimester. Among 661 spontaneous abortions, 15 twin pairs were identified including two sets of conjoined twins. Analysis of Q-band variants permitted the exclusion of cases with two cell lines that could be attributed to maternal contamination or mosaicism. The twinning rate among spontaneous abortions was 1/44 compared with 1/103 live births and stillbirths in the Ontario population. If Weinberg's differential method is applied to these data, the frequency would be as high as 1/30 under the assumption that the incidence of monozygotic twins among abortions is the same as that for live births.