A chromosomal translocation t(11;14) (p15;q11) is described in a human acute T‐cell leukaemia of immature phenotype (CD3‐, CD4‐, CD8‐). The translocation occurs at a T‐cell receptor joining J delta segment, 12 kb upstream of the constant C delta gene and 98 kb upstream of the C alpha gene at chromosome band 14q11. Nucleotide sequencing shows that both J delta and C delta are very conserved between mouse and man. The region of chromosome 11 involved in the translocation is transcriptionally active and produces a 4‐kb mRNA. The DNA sequence at the chromosome 11 junction shows a perfect match to a recombinase signal sequence implying that this translocation occurred by recombinase error. The occurrence of the translocation breakpoint at the C delta locus, normally rearranged in immature T cells, and the structure of the translocation junctions suggests that the translocation occurred during an attempt at normal rearrangement of the J delta segment in an early thymocyte.

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Objective To analyse the results of the first 2 years of a QF-PCR stand-alone testing strategy for the prenatal diagnosis of aneuploidy in the London region and to determine the advantages and disadvantages of this policy.Methods A review of the results of 9737 prenatal samples received for exclusion of chromosome abnormalities. All samples were subjected to QF-PCR testing for common aneuploidies but only samples fulfilling specific criteria subsequently had a full karyotype analysis. ResultsOf the 9737 samples received, 10.3% had a chromosome abnormality detected by QF-PCR testing. Of the 7284 samples received with no indication for karyotype analysis, 25 (0.3%) received a normal QF-PCR result but subsequently had an abnormal karyotype detected either prenatally as a privately funded test or postnatally. Of these samples, without subsequent abnormal ultrasound findings, five had a chromosome abnormality associated with a poor prognosis, representing 0.069% of samples referred for Down syndrome testing.Conclusion While back-up karyotyping is required for some samples, using QF-PCR as a stand-alone prenatal test for pregnancies without ultrasound abnormalities reduces costs, provides rapid delivery of results, and avoids ambiguous and uncertain karyotype results, reducing parental anxiety.

Eighty-four patients with typical chronic lymphocytic leukemia 27% of patients with B-CLL. [11][12][13] Fegan et al 13 studied 45 (CLL) (by morphological and immunophenotypic criteria) on patients with typical CLL over 5 years and performed cytowhom karyotypes were available were studied. Binet stage at genetic analysis every 6-12 months or more frequently if there diagnosis and follow-up were defined. Survival was calculated was evidence of disease progression. Abnormalities were from diagnosis. Fifty-one percent of patients had a karyotypic detected in 62% at some point during the study with 38% abnormality, the commonest being abnormalities at 13q14 (16%); these patients did not have significantly different surshowing clonal evolution. 11q deletions were found most frevival from patients with normal karyotype. The second comquently in the patients with progressive disease. This original monest abnormality was del(11q) (13%); these patients had sigstudy was extended to an adjacent centre and here we present nificantly worse survival when compared both with patients our updated long-term results. The patients' records were examined and the Binet stage was with CLL have chromosomal abnormalities as detected by noted at diagnosis and any change was documented. Treatcytogenetic analysis 1,2 but few centres perform routine cytogments for CLL were also recorded as were the causes of death. enetic analysis because of the perception that limited prognos-A patient was considered to have had a CLL-related death if tic information can be gained over and above that of the he/she died as a result of cytopenias, high-grade lymphoma Binet/Rai staging. The presence of a clonal abnormality, howor infection; also if CLL was quoted as the cause of death on ever, may be an aid in the diagnosis and assessment of progthe death certificate. Otherwise death was considered nonnosis. Deletions at 13q14 are the most frequent abnormality CLL related. In all cases survival was assessed from diagnosis. in CLL and occur in up to 30% of patients. 2-4 Such patients have been shown to have a similar survival pattern to those with a normal karyotype. 2 Trisomy 12 is another common abnormality, affecting about 20% of patients as determined Diagnosis of CLL by conventional techniques 2 but as many as 30-40% when analysed by FISH, detecting abnormalities in previously norThis required a peripheral lymphocytosis (Ͼ4 × 10 9 /l) of small mal karyotypes. 5,6 Trisomy 12 is thought to be an adverse mature lymphocytes, Ͻ10% prolymphocytes or large lymphoprognostic feature and correlation with atypical morphology cytes and Ͻ15% cleaved or lymphoplasmacytic cells. and poor survival has been shown. 2,6,7 Multiple karyotypic Immunophenotype of typical CLL was needed ie CD5, CD19 abnormalities, a high percentage of abnormal metaphases and and CD23 positive with weak immunoglobulin expression abnormalities of chromosome 14 are also associated with demonstrating or restriction. FMC7 was weak and/or poorer outlook; 2,8-10 at least a proportion of the latter wi...

Distal deletion of chromosome 3p25-pter (3p− syndrome) produces a distinct clinical syndrome characterised by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typically atrioventricular septal defect (AVSD), occurs in about a third of patients. In total, approximately 25 cases of 3p− syndrome have been reported world wide. We previously analysed five cases and showed that (1) the 3p25-pter deletions were variable and (2) the presence of CHD correlated with the proximal extent of the deletion, mapping a CHD gene centromeric to D3S18. To define the molecular pathology of the 3p− syndrome further, we have now proceeded to analyse the deletion region in a total of 10 patients (five with CHD), using a combination of FISH analysis and polymorphic markers, for up to 21 loci from 3p25-p26. These additional investigations further supported the location of an AVSD locus within 3p25 and refined its localisation. Thus, the critical region was reduced to an interval between D3S1263 and D3S3594. Candidate 3p25 CHD genes, such as PMCA2 (ATP2B2), fibulin 2, TIMP4, and Sec13R, were shown to map outside the target interval. Additionally, the critical region for the phenotypic features of the 3p− phenotype was mapped to D3S1317 to D3S17 (19-21 cM). These findings will accelerate the identification of the 3p25 CHD susceptibility locus and facilitate investigations of the role of this locus in non-syndromic AVSDs, which are a common form of familial and isolated CHD. (J Med Genet 2000;37:581-587)

Objective To investigate an approach for the analysis of samples obtained in screening for trisomy 21 that retains the advantages of quantitative fluorescent polymerase chain reaction (qf-PCR) over full karyotyping and maximises the detection of clinically significant abnormalities. Design Observational study. Setting Tertiary referral centre. Subjects 17 446 pregnancies, from which chorionic villous samples had been taken after assessment of risk for trisomy 21 by measurement of fetal nuchal translucency (NT) thickness at 11 to 13 +6 weeks of gestation. Interventions Analysis of chorionic villous samples by full karyotyping and by qf-PCR for chromosomes 13, 18, 21, X, and Y. Main outcome measure Detection of clinically significant chromosomal abnormalities. Results The fetal karyotype was normal in 15 548 (89.1%) cases and abnormal in 1898 (10.9%) cases, including 1722 with a likely clinically significant adverse outcome. Karyotyping all cases would lead to the diagnosis of all clinically significant abnormalities, and a policy of relying entirely on qf-PCR would lead to the diagnosis of 97.9% of abnormalities. An alternative strategy whereby qf-PCR is the main method of analysis and full karyotyping is reserved for those cases with a minimum fetal NT thickness of 4 mm would require full karyotyping in 10.1% of the cases, would identify 99.0% of the significant abnormalities, and would cost 60% less than full karyotyping for all. Conclusions In the diagnosis of chromosomal abnormalities after first trimester screening for trisomy 21, a policy of qf-PCR for all samples and karyotyping only if the fetal NT thickness is increased would reduce the economic costs, provide rapid delivery of results, and identify 99% of the clinically significant chromosomal abnormalities.

Objective To assess the implications of a change in prenatal diagnosis policy from full karyotype analysis to rapid trisomy testing for women referred primarily for increased risk of Down's Syndrome. Design Retrospective collection and review of data.Setting The four London Regional Genetics Centres.Population Pregnant women (32,674) in the London area having invasive prenatal diagnosis during a six-year three-month period. Methods Abnormal karyotypes and total number of samples referred for raised maternal age, raised risk of Down's Syndrome following serum screening or maternal anxiety were collected. Abnormal karyotypes detected by molecular trisomy detection were removed, leaving cases with residual abnormal karyotypes. These were assessed for their clinical significance. Pregnancy outcomes were ascertained by reviewing patient notes or by contacting obstetricians or general practioners. Main outcome measures Proportion of prenatal samples with abnormal karyotypes that would not have been detected by rapid trisomy testing, and the outcome of those pregnancies with abnormal karyotypes. Results Results from 32,674 samples were identified, of which 24,891 (76.2%) were from women referred primarily for Down's Syndrome testing. There were 118/24,891 (0.47%) abnormal sex chromosome karyotypes. Of the samples with autosomal abnormalities that would not be detected by rapid trisomy testing, 153/24,891 (0.61%) were in pregnancies referred primarily for Down's Syndrome testing. Of these, 98 (0.39%) had a good prognosis (46/98 liveborn, 3/98 terminations, 1/98 intrauterine death, 1/98 miscarriage, 47/98 not ascertained); 37 (0.15%) had an uncertain prognosis (20/37 liveborn, 5/37 terminations; 12/37 not ascertained) and 18 (0.07%) had a poor prognosis (1/18 liveborn, 2/18 miscarriage, 11/18 terminations, 4/18 not ascertained). Conclusions For pregnant women with a raised risk of Down's Syndrome, a change of policy from full karyotype analysis to rapid trisomy testing would result in the failure to detect chromosome abnormalities likely to have serious clinical significance in approximately 0.06% (1 in 1659) cases. However, it should be noted that this figure may be higher (up to 0.12%; 1 in 833) if there were fetal abnormalities in some of the pregnancies in the uncertain prognosis group for which outcome information was not available.

Summary Objective Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.