We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.

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.

Males affected by one form of X-linked retardation possess the X-chromosomal marker fra(X)(q27) and are physically normal except for macro-orchidism. To relate possession of the marker X to phenotypic expression in female heterozygotes, we investigated 128 mildly retarded (IQ, 55 to 75) school-girls in Sydney, New South Wales, Australia. Seventy-two girls had no physical abnormalities and of these, five (7 per cent) carried the marker X. Investigation of relatives revealed retarded males in four of the five families. Pedigree and chromosomal analysis identified a further 18 heterozygotes; six were regarded as intellectually or educationally retarded. We conclude that expression of the X-linked mutation in female carriers contributes to mild mental retardation of girls, that those who are physically normal should be screened for the marker X, and that their relatives should be investigated in order to identify additional females with a high risk of conceiving affected males.

In 3,000 women referred for prenatal diagnosis, 110(3.7%) abnormal fetuses were detected and 85 therapeutic terminations were performed. These were five main reasons for referral. Among the 2,227 women referred because of maternal age 35 years and older, there were 51 (2.3%) who had aneuploid fetuses. In the 297 women referred because of a previous child with Down syndrome, 3 aneuploid fetuses (1.0%) were detected. Of the 55 couples where one spouse was a carrier of a balanced chromosome rearrangement, 6 chromosomally abnormal fetuses were found (10.9%) (all the offspring of maternal carriers). In the latter group, five of the six heterozygotes with abnormal findings were carriers of tdic (13;21) translocations. In the 82 cases with a history of X-linked disorders, there were 40 males (49%). Thirty-five women were referred because of inborn errors of metabolism: 10 affected fetuses were found (28%). There was a greater proportion of sex-chromosome aneuploids as compared to trisomy 21 fetuses in the 35 to 39 year maternal age group. This was reversed in the group of women 40 years old and older. Of the 25 abnormal fetuses not terminated, 6 were sex chromosome aneuploids and 10 involved X-linked conditions where the progeny could be further prenatally monitored (eg, X-linked hydrocephalus) or treated (eg, hemophilia). In the remaining 9 the parents expressed divers reasons for their choice. Repeat amniocentesis was required in 2.9% of cases. One case of maternal cell contamination and one case of unconfirmed mosaicism were the only diagnostic errors found in the study. In the last 1,000 specimens referred, the average time necessary for a karyotypic result was 15.6 +/- 5.6 days after amniocentesis.