Linkage disequilibrium and recombination make a telomeric site for the Huntington''s disease gene unlikely.

In a Scottish family in which Huntington's disease (HD) was segregating, recombination was observed between the D4S115/S111 and D4S43/S95 loci, with the HD gene associated with the more proximal D4S43/S95 locus. Analysis of linkage disequilibrium in Scottish families showed significant non-random association between the HD gene and alleles at the D4S95 and D4S98 loci. This adds to previous evidence that the HD locus is not sited at the telomere of chromosome 4.     

Primary nodal marginal zone B-cell lymphoma arising from more than one clonal neoplastic population

Primary nodal marginal zone B-cell lymphoma is an uncommon monoclonal B-cell lymphoproliferative disorder. We report a case of a 79-year-old woman who presented with generalized lymphadenopathy. Histologic and immunohistochemical examinations of biopsy sections from an axillary lymph node were consistent with nodal marginal zone B-cell lymphoma. Flow cytometry analysis showed 2 distinct clonal B-cell populations expressing lambda or kappa light chain restriction. Subsequently, genomic deoxyribonucleic acid (DNA) isolated from a paraffin-embedded lymph node section was analyzed for the presence of gene rearrangements. Polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain genes revealed 3 rearranged DNA bands, confirming the presence of more than one clonal B-cell population. These immunophenotypic and genotypic findings have not been previously described in association with this type of lymphoma. To our knowledge, this represents the first reported case of biclonal nodal marginal zone B-cell lymphoma.     

Mapping of a gene (MRXS9) for X-linked mental retardation, microcephaly, and variably short stature to Xq12-q21.31.

Three boys from two families were identified as having a syndrome of X-linked mental retardation (XLMR) with microcephaly and short stature, clinically resembling Renpenning syndrome but with normal size of testicles in affected men. When the effort to map the gene for the above condition was initiated, it was realized that the two families were actually related to each other. Over 50 polymorphic markers of known locations along the X chromosome were scored in this family in a study to map the disease gene. Nine affected and four unaffected males were genotyped to produce a maximum LOD score of 4.42 at zero recombination with markers in proximal Xq. The results indicate that the gene responsible for this disorder is located in the cytogenetic Xq12 to Xq21.31 interval of the X chromosome within a section of chromosome of about 17 cM between the AR and DXS1217 loci over some 25 mb. Since the gene for the X-linked mental retardation from the original Saskatchewan family described by Renpenning [Renpenning et al., 1962: Can Med Assoc J 87:954-956; Fox and Gerrard, 1980: Am J Med Genet 7:491-495] was recently mapped to a different nonoverlapping region [Stevenson et al., 1998: Am J Hum Genet 62:1092-1101] this would appear to be a separate disorder.     

Development and Characterization of Reference Materials for MTHFR,SERPINA1, RET,BRCA1, and BRCA2 Genetic Testing

Well-characterized reference materials (RMs) are integral in maintaining clinical laboratory quality assurance for genetic testing. These RMs can be used for quality control, monitoring of test performance, test validation, and proficiency testing of DNA-based genetic tests. To address the need for such materials, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Coordination Program (GeT-RM), which works with the genetics community to improve public availability of characterized RMs for genetic testing. To date, the GeT-RM program has coordinated the characterization of publicly available genomic DNA RMs for a number of disorders, including cystic fibrosis, Huntington disease, fragile X, and several genetic conditions with relatively high prevalence in the Ashkenazi Jewish population. Genotypic information about a number of other cell lines has been collected and is also available. The present study includes the development and commutability/genotype characterization of 10 DNA samples for clinically relevant mutations or sequence variants in the following genes: MTHFR; SERPINA1; RET; BRCA1; and BRCA2. DNA samples were analyzed by 19 clinical genetic laboratories using a variety of assays and technology platforms. Concordance was 100% for all samples, with no differences observed between laboratories using different methods. All DNA samples are available from Coriell Cell Repositories and characterization information can be found on the GeT-RM website.The use of genetic tests in medical practice has increased rapidly over the past few years. There are currently over 1400 genetic tests offered in clinical laboratories and hundreds of additional tests are available in research settings (National Institutes of Health, http://www.genetests.com, last accessed March 2, 2009). As for all medical testing, laboratories performing genetic tests must adhere to established quality assurance practices to ensure confidence in test integrity and accuracy.¹ An integral part of quality assurance is the use of characterized and readily available reference materials (RMs). RMs, such as characterized DNA or cell lines that have a defined property, such as commutability (the equivalency of results between different measurement procedures) or genotype, can be used for quality control, monitoring of test performance, detection of errors, and proficiency testing of DNA-based genetic tests.^1,2,3A hierarchy of RMs has previously been described based on the degree of characterization of each material.^3,4,5,6 The top hierarchy includes Standard Reference Materials (SRMs), which are produced by the National Institute of Standards and Technology (NIST); Certified Reference Materials (CRMs), produced by several organizations including the Institute of Reference Materials and Measurements; and other materials available from independent organizations, such as the World Health Organization. These RMs possess properties that are certified by a procedure that establishes metrological traceability and degree of uncertainty.^3,4,5,6 These materials have also been extensively characterized to ensure their homogeneity and stability. On the next level of the hierarchy are those RMs whose properties are sufficiently homogeneous and established for use in quality control applications.⁴ These materials include some commercially available RMs, which have either been cleared by the US Food and Drug Administration (FDA) or CE-marked (a mandatory conformity mark for products placed within the European Union market), and are therefore cleared for in vitro diagnostic use. For the purposes of this article, we will call SRMs, CRMs, FDA-approved, and CE-marked RMs “higher order” RMs. The use of “higher order” in this article does not represent a technical definition but only a categorization. Some manufacturers and governmental organizations have developed higher order RMs for a small number of diseases 5 Though not higher order RMs, these genomic DNA or cell line materials play a vital role in quality control by providing a publicly available, renewable, and inexpensive source of RMs for various laboratory quality assurance needs.

Table 1

Publicly Available Higher Order RMs

Cardiac resynchronization therapy: left or left-and-right for optimal symptomatic effect--the LOLA ROSE study.

AIMS: Biventricular (BiV) pacing and left univentricular (LUV) pacing can each produce clinical benefits in heart failure. The impact of modern refinements in pacing optimization on the relative benefits of these two modes is unknown. We aimed to compare these two modes in patients with heart failure, using Echo-based optimization of each pacing mode. METHODS AND RESULTS: Paired data were collected on 18 patients (age 72 +/- 8 years; 16 male) with refractory heart failure symptoms, sinus rhythm, and LBBB with QRS duration>120 ms. Patients were randomized to an initial 8 weeks of either BiV or LUV pacing, followed by 8 weeks of the other mode, in a blinded cross-over design. Echocardiography was used to optimize atrioventricular delay for both modes and right ventricular-left ventricular offset for BiV mode. Peak oxygen consumption (baseline 13.6 +/- 2.7; BiV 15.8 +/- 3.0; LUV 15.2 +/- 3.1 mL/kg/min), 6 min walk distance (baseline 258 +/- 47; BiV 290 +/- 63; LUV 287 +/- 69 m), and scores on SF36 health questionnaire (baseline 41.5 +/- 16.8; BiV 58.6 +/- 19.6; LUV 51.8 +/- 21.3) did not differ between BiV and LUV modes. New York Heart Association class was significantly better in BiV than in LUV mode (P < 0.01). CONCLUSION: In this pilot study, we found no differences in major clinical outcome measures between the two modes of resynchronization.     

Nosocomial diarrhoea due to a single strain of Clostridium difficile: a prolonged outbreak in elderly patients.

An outbreak of diarrhoea occurred in an acute geriatric ward of a hospital (A). It affected six patients initially and was found to be due to a single strain of Clostridium difficile. There was little evidence for asymptomatic carriage of this strain or others in the hospital patients. The following three months saw an increase in the number of symptomatic cases of C. difficile disease in two peripheral hospitals, B and C. Patients had been moved from the outbreak ward to these hospitals. Of 18 cases in hospital B all 15 isolates saved for typing were of the 'outbreak' strain. Of three cases occurring in hospital C, only one was the 'outbreak' strain (a relapsed patient who was part of the original episode). There were seven further cases in geriatric and medical wards of hospital A. All six typed isolates were also the outbreak strain. By chance, four isolates from hospital A and four from hospital B pre-dating the outbreak were also available for typing and seven of these were found to be identical to the outbreak strain. This suggests that one strain of C. difficile was endemic in geriatric and medical facilities on two sites and was responsible for nosocomial diarrhoea over at least one year. The problems of optimal management and infection control in this situation are discussed.     

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: A second FG locus [FGS2]?

FG syndrome is an X‐linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints. Am. J. Med. Genet. 95:178–181, 2000. © 2000 Wiley‐Liss, Inc.