Eeva Therman

The critical region on the human Xq

SummaryAdult female carriers of balanced X; autosome translocations (118 cases) and of balanced X inversions (31 cases) have been collected from the literature. Forty-five of the 118 translocation carriers in whom the break was in the critical region (Xq13–q22, Xq22–q26, separated by a narrow region within Xq22) showed gonadal dysgenesis. Seven of the 31 inversion carriers in whom the break was in the same region also had gonadal dysgenesis, whereas the remaining 24 were normal in this respect. The critical region consists mainly of Q-bright material, and is the fifth brightest segment in the human genome. The region contains relatively few genes. It is possible that meiotic crossing-over, rarely, if ever, takes place in it. The critical region may therefore consist of two “supergenes” whose integrity must be maintained to allow normal ovarian development. The effect exerted by this region differs from other known position effects, in that it is independent of the break-point within the region and of the chromosome bands to which the broken ends are attached. One possible mechanism causing this effect might be a change in the replication order of the chromosome bands, which, in turn, might affect their function.

A new autosomal trisomy syndrome: multiple congenital anomalies caused by an extra chromosome

Summary Two patients are described who died in early infancy. Each displayed similar complexes of congenital anomalies of which the following ones were found in both: low-set and malformed ears, small mandible, flexion deformities of the fingers, anomalous feet, interventricular septal defect, spasticity with probable mental defect, and diverticulum of the intestine. The chromosome number was 47, the extra chromosome appearing to be the same one in each instance; it belongs to the E group in the classification of Patau and associates. 1 The mothers of both patients were of advanced age at the time of conception.

Abnormal X chromosomes in man: Origin, behavior and effects

SummaryAbnormal human X chromosomes, their origin, phenotypic effects, and especially their inactivation are reviewed. In cases of balanced reciprocal X-autosomal translocations (Table 2), almost always the normal X is inactivated. Most of such patients suffer from gonadal dysgenesis, which might be caused either by functional hemizygosity for a recessive gene or by a position effect resulting from a rearrangement involving a certain region of Xq. In cases with 46 chromosomes and an unbalanced X-X translocation, the translocation chromosome is inactivated; in most such patients, an X0 cell line is also present (Table 3). Some of the possible modes of origin of such translocations are presented in Fig. 1; these also explain the occurrence of the X0 cell lines. In patients with 46 chromosomes and an unbalanced X-autosomal translocation, the whole translocation chromosome seems to be inactivated, if the autosomal segment is attached to Xp. If on the other hand the segment is, attached to Xq, inactivation seems to be limited to the X part (Fig. 3).There are reasons for assuming the existence of an inactivation center without which an X chromosome cannot be inactivated. This center would be located on the proximal part of Xq. (Abnormal chromosomes with two such centers tend to form bipartite Barr bodies.) If 2 X chromosomes possess an inactivation center each, they would originally be inactivated at random, it then being left to selection to determine the final frequencies of the cell lines with different inactivation patterns.The phenotypic effects of monosomy, disomy and trisomy for different parts of Xp and Xq are discussed (Fig. 3).

The D1 trisomy syndrome

This paper further defines the phenotype which results from trisomy for a particular autosome of the D group (13–15) in the cells of the developing embryo. From our 7 patients plus 7 additional cases reported by others, the principal pattern of anomalies in these grossly malformed babies is presented. Though there is variability in the expression of the D 1 trisomy from patient to patient, the total pattern of anomalies is specific enough to allow for clinical recognition in the nursery for newborn infants. As with the other autosomal trisomy syndromes (Downs syndrome and the 18 trisomy syndrome), this condition occurs more commonly at older maternal age.

The No. 18 trisomy syndrome.

Summary Trisomy of chromosome No. 18 results in a characteristic pattern of multiple congenital anomalies of which apparent mental retardation with moderate hypertonicity, lowset malformed ears, small mandible, flexion of the fingers with the index finger overlying the third, and severe failure to thrive constitute the most prominent clinical abnormalities. It usually leads to death in early infancy. The syndrome has been of sporadic occurrence. Its frequency increases with advancing maternal age.

The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis

SummaryWe have collected from the literature adult nonmosaic women with the following aberrant X chromosomes: Xp- (52), Xq- (67), idic(Xp-)(10), idic(Xq-)(9), and interstitial deletions (12). Lack of Xp, and especially Xcen-Xp11 (b region), may cause full-blown Turner syndrome. However, individual Turner symptoms, including gonadal dysgenesis, otherwise seem to be randomly distributed with respect to the different Xp and Xq deletions, although breakpoints distal to Xq25 do not give rise to any phenotypic anomalies except in a few cases of secondary amenorrhea or premature menopause. Of the carriers of an Xp- or Xq- chromosome, 65% and 93%, respectively, suffer from ovarian dysgenesis, whereas all idic(Xp-) and idic(Xq-) chromosomes cause primary or secondary amenorrhea. Xq deletions do not induce specific symptoms different from those caused by Xp deletions. Lack of the tip of Xp has led in 46/52 cases to short stature, but 43% of the Xq- carriers are also short. To explain these observations, we propose the following hypothesis. Since deletions of truly inactivated regions do not seem to cause any symptoms, we assume that the b region (Xcen-p11) always stays active in a normal inactive X, but is inactivated in deleted X chromosomes, especially in Xq- chromosomes. In some cases, inactivation may spread to the tip of Xp; this would explain the apparently variable behavior of the Xg and STS genes, and the short stature of some Xq- carriers. Full chromosome pairing seems to be a prerequisite for the viability of oocytes and thus for gonadal development. Deleted X chromosomes necessarily leave a portion of the normal X unpaired and isodicentrics probably interfere with pairing, resulting in atresia of oocytes. The role played by the “critical region” (Xq13–q24) in ovarian development is still unclear.

X chromosome constitution and the human female phenotype

SummaryThe correlations of abnormal X chromosome constitutions and the resulting phenotypes in the human female are reviewed. The following hypotheses put forward to explain these correlations are discussed in detail: (1) The damage is done before X inactivation; (2) An effect is exerted between reactivation of the X chromosome(s) and meiosis in oocytes; (3) A recessive gene(s) in hemizygous condition might be expressed in the cases in which the same X is active in all cells; (4) A change in the number of presumed active regions on the inactive X chromosomes might have an effect; (5) A position effect, in that the region Xq13-q27 has to be intact in both X chromosomes to allow normal development, may be responsible; (6) An effect during the period when cells with different inactivation patterns compete is a probability; (7) The original X inactivation may be neither regular nor random.The conclusion reached is that the phenotypic effects of a specific X chromosome aberration may be simultaneously exerted through different pathways (Tables 1 and 2). Hypotheses (2), (4), (5), and (6) are considered probable. Hypothesis (3) has been discarded, and there is very little evidence for hypotheses (1) and (7).

Center for Barr body condensation on the proximal part of the human Xq: a hypothesis

The following hypothesis is put forward: X chromatin in man condenses around a center which is situated on Xq at a short distance from the centromere. The hypothesis is based on, and explains, two classes of observations. (1) Abnormal X chromosomes that have the assumed center in duplicate form bipartite Barr bodies in part of the cells. The frequency of bipartite bodies and the distance between the two parts seem to be determined by the distance between the postulated centers. (2) A large number of variously abnormal X chromosomes have been described. Almost all of them possess the postulated center and it seems possible that the very few apparent exceptions represent misidentifications of chromosome Xq — as isochromosome i(Xp). According to the hypothesis, chromosomes lacking the center would form no Barr body and therefore presumably would not be inactivated, thus leaving the cell severely unbalanced. Furthermore, absence of the center might interfere with the viability of the chromosome itself.

Partial-trisomy syndromes

SummaryOne of the autosomes of the C group (6–12), C′, can sometimes be identified by a secondary constriction.A mother and her daughter, both afflicted with the oral-facialdigital (OPD) syndrome, are shown to be partially trisomic for an inner segment of C′, this segment having been inserted into chromosome 1. The other chromosome 1, the two chromosomes C′, and the rest of the complement of 46 chromosomes appear normal.In four other OFD patients no chromosomal abnormality was detected. Nonetheless, it is concluded that the OFD syndrome is generally caused by partial trisomy for a specific region of C′. The presence of the inserted extra segment would usually escape microscopical detection.

Dicentric chromosomes and the inactivation of the centromere.

SummaryThe origin and behavior of human dicentric chromosomes are reviewed. Most dicentrics between two non-homologous or two homologous chromosomes (isodicentrics), which are permanent members of a chromosome complement, probably originate from segregation of an adjacent quadriradial; such configurations are the result of a chromatid translocation between two nonhomologous chromosomes, or they represent an adjacent counterpart of a mitotic chiasma. The segregation of such a quadriradial may also give rise to a cell line monosomic for the chromosome concerned (e.g., a 45,X line). Contrary to the generally held opinion, isodicentrics rarely result from an isolocal break in two chromatids followed by rejoining of sister chromatids. In this case the daughter centromeres go to opposite poles in the next anaphase, and the resulting bridge breaks at a random point. This mechanism, therefore, leads to the formation of an isodicentric chromosome only if the two centromeres are close together, or if one centromere is immediately inactivated. Observations on the origin of dicentrics in Bloom syndrome support these conclusions. One centromere is permanently inactivated in most dicentric chromosomes, and even when the dicentric breaks into two chromosomes, the centromere is not reactivated. The appearance and behavior of the “acentric” X chromosomes show that their centromeres are similarly inactivated and not prematurely divided. Two Bloom syndrome lymphocytes, one with an extra chromosome 2 and the other with an extra chromosome 7, each having an inactivated centromere, show that this can also happen in monocentric autosomes.