Data on 1,237 prenatal (amniocyte) diagnoses in cases of familial chromosome rearrangements were collated from 79 American and Canadian laboratories. These were added to European data (Daniel et al: Prenatal Diagn 6:315-350, 1986) on 596 reciprocal translocations (rcp) from 71 collaborative laboratories. The total data set was examined for relationships between balanced or unbalanced result and mode of ascertainment, sex of carrier parent, chromosomes involved, and (in cases of reciprocal translocations and pericentric inversions) for potential or actual chromosome imbalance size (% haploid autosome length). Risk rates for unbalanced segregants were markedly dissimilar. These ranged from approximately 50% down to essentially a negligible risk. The risk was approximately 50% for carriers of the following: complex chromosome rearrangements (ccr); insertions (ins); and for 2:2 segregating rcp ascertained by mode 1 (term unbalanced proband) with small imbalance segments. Pooled carriers (either sex) of 2:2 segregating rcp of mode 1 had a risk of 20-25% whereas female Robertsonian (rob) translocation (D;21) carriers and pericentric inversion (pii) carriers of pii with small distal segments had a risk of 10-15%. Pooled 2:2 segregating rcp carriers ascertained by mode 2 (a couple with recurrent miscarriages) and male carriers of rob (D;21) had a risk of 1.5-5%. The risk of unbalanced segregants was 1-2% (in this data) for male and female rob (13;14) carriers and for pooled pericentric inversion carriers. However, for carriers of most "type" (recurrent breakpoints) pii, for all paracentric inversions, and (as expected) for rob not involving 13 or 21, there were no term unbalanced progeny. For 2:2 segregating reciprocal translocations plots were prepared that could be used to determine broad risk groups for carriers of such rcp. In 3:1 segregating rcp there were 3.3 times fewer male than female carriers, whereas there were 1.3 times fewer male carriers in 2:2 segregating rcp. In 2:2 segregating rcp there is little effect on the fertility of male carriers and risks of unbalanced progeny were found to be equal to those for female carriers, whereas in the 3:1 segregating rcp, risks were much less for male as compared to female carriers. This indicates that 3:1 segregating rep are more similar to Robertsonian translocations in their greater effect on the fertility of male carriers.(ABSTRACT TRUNCATED AT 400 WORDS)
We report on 11 cases of isochromosome 12p mosaicism (or Pallister mosaic aneuploidy syndrome) in which the isochromosome is usually absent in cultured lymphocytes but present in fibroblasts. The patients range in age from a 22-week-gestation fetus to a 45-year-old man. They have a distinct pattern of anomalies which enables one to make a diagnosis based on clinical manifestations alone. Craniofacial manifestations include "coarse" face with prominent forehead, sparsity of scalp hair, hypertelorism, epicanthal folds, flat bridge of nose, and highly arched palate. Affected newborn infants are profoundly hypotonic with sparsity of scalp hair especially bitemporally and a prominent forehead. Most have accessory nipples. Birthweight and growth parameters are usually normal; however, some newborn infants are unusually large. In infancy, the facial appearance becomes "coarse," hypotonia persists, and seizures may occur. As adults, growth may be normal, scalp hair is thicker and the mandible becomes prominent. Most have a generalized pigmentary dysplasia which may be evident with a Wood's lamp only. All cases have been sporadic and there is no consistent pattern of advanced parental age.
Fourteen marker chromosomes were studied by FISH (fluorescence in-situ hybridization) in cytogenetic preparations from 13 patients. The derived markers were identified as one isodicentric bisatellited mar(22), one fragment sized r(X), one fragment sized r(Y), one i(18p), small autosomal ring markers in three different patients derived from chromosomes 2, 8, and 8, a marker comprised of 9p and part of 9qh, and 3 bisatellited apparently monocentric markers; one of each from chromosomes 13 or 21, 14 or 22, and 15. Two fragment sized small ring markers in one patient and a small ring marker in another were negative with all twenty-two different probes used. In addition, the small ring marker Y chromosome that was found in a boy with karyotype 46,X,-Y,+mar was negative with both pDXZ1 and pDYZ3. This anomaly of negative results with the battery of centromeric alphoid probes can be explained if one breakpoint for some small ring markers is very near to or within the centromere. Only some of the pericentromeric repetitive sequences in the normal chromosome would be represented in the chromosome specific alphoid probes, and presumably those corresponding to the currently available probes are truncated during the formation of the unidentified markers. In three of the small ring markers the FISH signal on the marker was much stronger than on the normal homologues in various proportions of cells, and this may indicate that some of the fragment sized small rings were multicentric. The literature was reviewed for Distamycin A/DAPI negative small ring markers that were present as extra chromosomes. There were only single published cases of most small rings but there were three r(8) cases, two r(1) cases, two r(12) cases, and two r(20) cases, uncomplicated by the presence of other chromosome abnormalities. Most cases with similar small rings were quite dissimilar phenotypically and syndrome identification was not possible, but in pooled data, 18/23 (about 80%) were developmentally and/or phenotypically abnormal. Some patients (5/23, about 20%) with small rings were dysmorphic without intellectual handicap. Of 28 such patients with small ring markers (Distamycin/Dapi negative) in pooled data there are 6 (about 20%) with multiple markers mostly derived from different chromosomes. This is a very high figure and would suggest that the ring formation events, although involving different chromosomes, must be related and must be an indicator of the mechanism of origin of this group of markers.
An epidemiological study was carried out on the group of moderately retarded brothers (IQ, 30-55) identified by Turner and Turner [1974]. Of the original 58 sets of brothers, 54 sets (now 17 to 32 years old) were traced; another four sets (missed in the earlier survey) were added. Forty-five of the 58 pairs were diagnosed as having nonspecific X-linked mental retardation (MR) giving an overall frequency of 5.57 moderately retarded males/10,000 male births. In 12 of the 45 families, affected males had the fragile(X) and macroorchidism; six had macroorchidism alone, giving a frequency of 2.8 moderately retarded males with X-linked MR and macroorchidism +/- the fragile(X) per 10,000 males. Corresponding heterozygote frequencies are 7.34 and 3.65/10,000 females respectively. A new subgrouping of nonspecific X-linked mental retardation is described in six families: X-linked MR, macroorchidism without the fragile(X). Three other X-linked conditions were identified: in one family, the Coffin-Lowry syndrome, in another, Duchenne muscular dystrophy, and in two families X-linked MR and muscle atrophy. Half (56%) of the obligatory carriers of fra(X)-MR in this study were dull to mildly retarded. The mildly retarded heterozygotes had a significantly higher percentage of fra(X) expressing lymphocytes as compared to the intellectually normal heterozygotes. When the three types of nonspecific X-linked MR for which population frequencies were calculated were considered together, half of the obligatory carriers (46%) were dull or mildly retarded, thus confirming that this condition is a significant cause of mild intellectual handicap in females.
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