GESPA: classifying nsSNPs to predict disease association.

Background: Non-synonymous single nucleotide polymorphisms (nsSNPs) are the most common DNA sequence variation associated with disease in humans. Thus determining the clinical significance of each nsSNP is of great importance. Potential detrimental nsSNPs may be identified by genetic association studies or by functional analysis in the laboratory, both of which are expensive and time consuming.

ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group.

Background: ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway-associated factors in pediatric cases and cell lines.

Procedure: Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25).

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.

OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability.

Background/aims: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe.

Methods: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1.

Detection of FOXO1 (FKHR) gene break-apart by fluorescence in situ hybridization in formalin-fixed, paraffin-embedded alveolar rhabdomyosarcomas and its clinicopathologic correlation.

Chromosomal translocations of t(2;13)(q35;q14) and t(1;13)(p36;q14), resulting in PAX3-FOXO1 (FKHR) and PAX7-FOXO1 (FKHR) gene fusions, have been found to be specific molecular markers for alveolar rhabdomyosarcomas (ARMS) and can be identified in approximately 80% cases. As the prognosis of ARMS is worse than that of embryonal rhabdomyosarcomas (ERMS), it is important to accurately distinguish between these 2 subtypes. This distinction may be difficult on the basis of morphology alone.

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis.

Over 100 mutations in the presenilin-1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Abeta was identified in leptomeningeal vessels and in cerebral plaques.

A TNNI2 mutation in a family with distal arthrogryposis type 2B.

Linkage mapping in a three-generation family with a distal arthrogryposis (DA) phenotype intermediate between DA2A and DA1 indicated linkage to 11p15.5 but not 9p13. Follow up DNA sequencing of the TNNI2 gene detected a three base pair deletion that would be predicted to result in the deletion of a glutamic acid at codon position 167 (DeltaE167).

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin.

Genetically characterized positive control cell lines derived from residual clinical blood samples.

Background: Positive control materials for clinical diagnostic molecular genetic testing are in critically short supply. High-quality DNA that closely resembles DNA isolated from patient specimens can be obtained from Epstein-Barr virus (EBV)-transformed peripheral blood lymphocyte cell lines. Here we report the development of a process to (a) recover residual blood samples with clinically important mutations detected during routine medical care, (b) select samples likely to provide viable lymphocytes for EBV transformation, (c) establish stable cell lines and confirm the reported mutation(s), and (d) validate the cell lines for use as positive controls in clinical molecular genetic testing applications.

Dent Disease with mutations in OCRL1.

Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported.

Congenital vertical talus in four generations of the same family.

Objective: This paper presents four generations of a family with radiographically demonstrated congenital vertical talus (CVT) in whom a HOXD10 gene mutation was identified. Some members of the family with this mutation exhibited cavo-varus foot deformity consistent with a Charcot-Marie-Tooth (CMT)-like disorder.

Design And Patients: Physical examination was performed on nearly all of the affected and unaffected family members.

A new HLA-A1 mutation: a novel, null variant allele.

From an unusually informative family of 8 with near identical parental haplotypes (a and c), which differed by a single nucleotide substitution, we identified a new HLA-A1 null variant. While serologic antigen typing initially showed a "blank" allele in maternal haplotype "c" and 2 male offspring, more sophisticated DNA molecular HLA typing subsequently revealed the presence of a novel HLA-A0101 allele. Sequence-based typing showed a point mutation consisting of a nucleotide substitution of a cytosine for a guanine at nucleotide 215 yielding an amino acid change of arginine to proline at codon 48 in exon 2 (R48P).

A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease.

Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance.

Bioelectronic sensor technology for detection of cystic fibrosis and hereditary hemochromatosis mutations.

Context: Bioelectronic sensors, which combine microchip and biological components, are an emerging technology in clinical diagnostic testing. An electronic detection platform using DNA biochip technology (eSensor) is under development for molecular diagnostic applications. Owing to the novelty of these devices, demonstrations of their successful use in practical diagnostic applications are limited.

Cystic fibrosis: S158N (605G --> A) is a rare genetic variant found in coupling with deltaF508.

A single nucleotide change at codon 158 in exon 4 of the CFTR gene ABCC7 was detected in an asymptomatic individual who carried deltaF508 and had a family history of cystic fibrosis (CF). Further study, using linkage, revealed that S158N was coupled with deltaF508, both having been inherited from the same parent. The clinical implications of double mutations in the same allele are discussed.

Association between conformational mutations in neuroserpin and onset and severity of dementia.

Background: The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations.

Methods: Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination.

Molecular diagnosis of cystic fibrosis.

A review of the current molecular diagnosis of cystic fibrosis including an introduction to cystic fibrosis, the gene function, the phenotypic variation, who should be screened for which mutation, newborn and couple screening, quality assurance, phenotype-genotype correlation, methods and method limitations, options, statements, recommendations, useful Websites and treatments.