Molecular cytogenetic investigation of two patients with Y chromosome rearrangements and intellectual disability.

We describe two males with intellectual disability (ID) and facial dysmorphism, both of whom have non-mosaic Y chromosome rearrangements resulting in deletions of large portions of the Y chromosome. Patient A, with ID, mild dysmorphism, speech delay, Duane anomaly of the eye, hypermetropia and conductive hearing loss, had two structurally rearranged Y chromosomes resulting in both p and q arm deletions in addition to a Yp duplication. Patient B, also with speech and language delay, developmental delay and short stature, had an interstitial deletion of Yq11.21-11.23. Array-CGH excluded the presence of additional submicroscopic rearrangements at the 1 Mb resolution level. A review of males with Y chromosome rearrangements and ID was performed. Our study provides a more detailed molecular cytogenetic assessment of Y rearrangements in individuals with ID than has been previously possible, and facilitates assessment and comparison of other individuals with a Y chromosome rearrangement.

Testicular relapse of acute promyelocytic leukemia after allogeneic BMT.

After treatment of acute leukemia (typically ALL and the monocytic variants of AML), relapse may occur at sites other than the marrow. Isolated extramedullary relapse of acute promyelocytic leukemia (APL) however, is rare. We describe such an event in a man who underwent allogeneic BMT for APL in second relapse and 4 years later presented with testicular relapse. The marrow was morphologically and cytogenetically normal, but RT-PCR analysis revealed the specific PML/RAR chimeric RNA transcript.

Genetic stability of the D1Z2 region: implications for DNA genotyping and paternity testing.

The aim of the present study was to examine a single locus variable number tandem repeat for the purpose of DNA genotyping ("fingerprinting"). DNAs of 175 individuals from five ethnic groups (Black, Chinese, Japanese, Caucasian, and Melanesian) were analyzed. Restriction fragment length polymorphic analysis of random individuals revealed individual specific DNA patterns in all but one group. Among 20 Melanesian inhabitants of the Vanuatu islands in the southwest Pacific, three individuals were found to share a common pattern. This island population represents a "genetic isolate" and illustrates the importance of carrying out population studies on individual ethnic groups of interest. The complexity and the genetic stability of the D1Z2 region as revealed by the probe hMF1 make it an excellent candidate for DNA genotyping in paternity testing as 101 Caucasian individuals each had unique patterns for PstI and SinI digests.

Three cases of partial trisomy 7q owing to rare structural rearrangements of chromosome 7.

Three cases of partial trisomy 7q are described. One case had duplication of region 7q22.1----q31.2 owing to a de novo direct intra-arm intrachromosomal duplication. The other two cases, first cousins, were trisomic for 7q34----qter, resulting from recombination within the inserted segment of a dir ins(7;17)(q34;q23.1q25.3)mat. All three cases had a number of the already recorded manifestations of partial trisomy 7q, namely strabismus, low set ears, depressed nasal bridge, small nose, hypotonia, and mental retardation.

Chromosome damage by dothistromin in human peripheral blood lymphocyte cultures: a comparison with aflatoxin B1.

The clastogenic potential of the pine tree fungal toxin dothistromin was studied by metaphase chromosome analysis of stimulated human peripheral blood lymphocytes exposed in vitro. The frequency of gaps, breaks, deletions and exchanges was scored in a series of cultures from 3 different donors. 50 cells were analysed for each dose level on coded slides. Testing was performed with and without added metabolic activation (as S9 mix) and aflatoxin B1 was used as a positive control in all experiments. Dothistromin caused a dose-dependent increase in the frequency of gaps and deletions which was not dependent on added metabolic activation. Even at high doses of dothistromin only a very small number of complex exchange-type aberrations were seen. This is in contrast to aflatoxin B1 where such aberrations were seen at low dose levels and especially in cultures to which S9 mix was added. High doses of dothistromin caused culture toxicity manifesting as haemolysis of the donor red blood cells and reduction of mitotic index. Culture toxicity occurred without a marked increase in aberration frequency. This toxicity may be masking any major potential for clastogenicity by dothistromin.

New classes of common fragile sites induced by 5-azacytidine and bromodeoxyuridine.

Two new classes of common fragile site seen in chromosomes from blood lymphocyte cultures are reported. The first class is induced in bands 1q42 and 19q13 by 5-azacytidine (5-AZA). Maximum induction of these fragile sites occurs when the 5-AZA is added 5-8h prior to harvest. The second class is induced in bands 6q13, 9p21, and 10q21 by bromodeoxyuridine (BrdU). In this instance maximum induction occurred if the BrdU was added 4-6h prior to harvest. The known fragile sites, both rare and common, are summarised.

Improved radioassay for human antithyroglobulin.

Human antithyroglobulin (anti-HTg) in serum and tissue cultures can be assayed by coprecipitation with 125I-labelled human thyroglobulin (HTg). Co-precipitation of the antibody from different sera gives roughly parallel curves, so that a standard serum can be used for quantitiation of other sera. By assessing the binding of 125I-labelled HTg in antigen excess we estimate the antibody content of the standard serum to be 0.14 ng anti-HTg per ml. Shortened incubation minimizes non-specific binding of HTg to serum globulins and obviates pre-assay absorption of HTg. Radioassay for thyroglobulin antibodies in serum correlated with values obtained by solid-phase competitive-binding assay (SPCB). One unit in our assay corresponds to 0.014 unit by the latter assay and to 0.12 units of MRC. Research Standard A. We confirm that serum thyroglobulin seriously interferes with SPCB assay, giving what appears to be positive results for anti-HTg where none is detected with our assay. Values for anti-HTg are depressed by serum HTg but only in the presence of very high concentrations in serum.

Developmental changes in pituitary-thyroid function in the human fetus and newborn.

Maturation of the hypothalamic pituitary thyroid axis as reflected in cord serum thyroid hormone concentrations was assessed in premature and full term infants born between 26 and 43 weeks gestation. Measurements of thyroxine (T4), free T4 (FT4), thyrotropin (TSH) and thyroxine binding globulin (TBG) in cord sera were correlated with gestational age, sex and birthweight and compared to similar measurements in well two month old infants and adults. There were significant increases in T4, FT4, and TBG with increasing gestational age (GA) between 26 and 33-35 weeks (P less than 0.001). After 34 weeks, none of these parameters varied with GA. When the infants were separated on the basis of sex the linear regression curves describing the relationships between hormone and TBG concentrations and GA were not different from the curves in the total population. The mean FT4/TSH ratio increased significantly with age throughout gestation (P less than 0.01) and was significantly lower in cord blood samples than in blood samples from the 2-month-old infants or the adults. The results suggest that the set point for negative feedback control of TSH secretion at the pituitary level is changing between 26 weeks GA and 2 months of life. Thyroid gland sensitivity to TSH stimulation also appears to be increasing between 26 and 33 weeks GA.

Interstitial deletion of the long arm of chromosome no. 5 in two unrelated children with congenital anomalies and mental retardation.

Two unrelated children with partial deletion of the long arm of a chromosome no. 5 are reported. The boy presented with severe hypotonia, developmental delay, and a few minor defects of the face including frontal bossing, antimongoloid slant of the palpebral fissures, depressed nasal bridge and bilateral epicanthal folds. With age, his hypotonia has improved. The parents have normal chromosomes; the mother has a 9qh+ variant. The second patient, a girl, presented at birth with multiple congenital anomalies including cleft palate, epicanthal folds, anteverted nostrils, horseshoe kidneys and club feet. At 4 years of age, she was small and severely retarded. The normal parents and the normal sister showed no chromosomal abnormalities. Gene mapping studies in both patients failed to define a specific gene locus to the deleted chromosome regions. Including these two patients, there appear to be only three reported cases of patients with 5q deletion. A comparative description of the third patient is included in this report. There are some clinical similarities but these are inadequate to identify a clinical syndrome. This perhaps is explained by some quantitative and qualitative differences in the deletions.

Partial trisomy 9q due to maternal 9/17 translocation.

A patient with partial trisomy 9q due to material 9/17 translocation was studied and compared with four previously reported cases. The similarity of their clinical features allowed us to delineate a distinct clinical syndrome, which is characterized by psychomotor retardation, dolichocephaly, beaked nose, deep-seated eyes, and long fingers and toes. There is an overlap between some of the features of this syndrome and those of trisomy 9.

A deleted extra chromosome 22 identified by DNA replication banding.

The identification of a deleted extra chromosome 22 by means of the DNA replication banding pattern is reported. The characteristics of DNA replication banding, its advantages and superiority in chromosome identification are described.

The ring nature of a tiny supernumerary chromosome fragment.

We report a 5 1/2-year-old girl with a tiny supernumerary chromosome fragment found in mosaic. The ring nature of the tiny fragment was demonstrated by the detection of the characteristic products of a ring chromosome. The clinical consequence of a ring chromosome and the impact of finding a supernumerary chromosome fragment, especially in the practice of prenatal chromosome diagnosis, are discussed.

Complex de novo rearrangement of chromosome 9 with clinical features of monosomy 9p syndrome.

A girl with a complex rearrangement of chromosome 9 is reported. She shows the characteristic clinical features of monosomy 9p syndrome. The rearrangement was apparently preceded by four breaks which resulted in a presumptive tiny deletion of the distal end of the short arm, inversion of the rest of this arm and a proven deletion of the secondary constriction region of the long arm. By means of C-banding, it was possible to demonstrate the paternal origin of the rearranged chromosome 9. Finally, it is shown that the region determining the phenotypic expression of monosomy 9p syndrome is seemingly located at band 9p24.

Relation between the SCE points and the DNA replication bands.

A method for obtaining a combination of differential sister chromatid staining and DNA replication banding is described. Using this method the SCE points can be precisely localized to particular bands of individual chromosomes. It was shown, that SCEs occur not only in the regions of early DNA replication (= euchromatic segments = negative G-bands), but also in the regions of late DNA replication bands (=heterochromatic segments=positive G-bands). SCEs occurred about three times more frequently in the euchromatic segments than in the heterochromatic segments. Furthermore, more SCEs were observed in the early replicating X-chromosome than in the late replicating X-chromosome.

Combination of differential sister chromatid staining, G-banding pattern, and X-inactivation pattern.

A method is presented for obtaining a combination of differential sister chromatid staining. G-banding and X-chromosome inactivation pattern. The result of this method enables a precise localization of the sister chromatid exchange points to particular bands of individual chromosomes.

Two cases of trisomy 12p due to rcpt (12;21)(p11;p11) inherited through three generations.

Two cases of trisomy 12p due to a familial translocation t(12;21) (p11;p11) inherited through three generations are presented. The clinical features of both affected individuals are consistent with those previously reported. Study of the NORs by silver staining showed translocation of the NOR from chromosome 21 onto the der(12) and suggested that the activity of this site has been suppressed in some carriers.