Does the survival motor neuron copy number variation play a role in the onset and severity of sporadic amyotrophic lateral sclerosis in Malians?

Introduction: Spinal muscular atrophy (SMA) and sporadic amyotrophic lateral sclerosis (SALS) are both motor neuron disorders. SMA results from the deletion of the survival motor neuron () 1 gene. High or low copy number and the absence of have been reported as risk factors for the development or severity of SALS.

Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa.

Objective: Spinal muscular atrophy (SMA) is one of the most common severe hereditary diseases of infancy and early childhood in North America, Europe, and Asia. SMA is usually caused by deletions of the survival motor neuron 1 (SMN1) gene. A closely related gene, SMN2, modifies the disease severity.

A GC-wave correction algorithm that improves the analytical performance of aCGH.

Array-based comparative genome hybridization (aCGH) is a powerful, data-intensive technique used to identify genomic copy number variation throughout the human genome. The use of aCGH clinically to identify pathogenic copy number aberrations is becoming common, and the statistical and mathematical algorithms used in aCGH data analysis play an important role in determining the performance of these platforms. Interpretation of aCGH data can be complicated by a platform-independent technical artifact described as GC-waves, which are wave patterns in CGH data correlating to regional GC-content of the human genome that can reduce the clinical specificity and sensitivity of aCGH platforms.

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens.

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition.

Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.

It has been proposed that multiple rare variants in numerous genes collectively account for a substantial proportion of multifactorial inherited predisposition to a variety of diseases, including colorectal adenomas (CRA). We have studied this hypothesis by sequencing the adenomatous polyposis coli (APC) gene in 691 unrelated North American patients with CRAs and 969 matched healthy controls. Rare inherited nonsynonymous variants of APC were significantly overrepresented in patients who did not carry conventional pathogenic mutations in the APC or MutY homologue genes [non-familial adenomatous polyposis (FAP) non-MUTYH-associated polyposis (MAP) patients; 81 of 480, 16.

Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families.

Background: Large rearrangements account for 8% to 15% of deleterious BRCA mutations, although none have been characterized previously in individuals of Mexican ancestry.

Methods: DNA from 106 Hispanic patients without an identifiable BRCA mutation by exonic sequence analysis was subjected to multiplexed quantitative differential PCR. One case of Native American and African American ancestry was identified via multiplex ligation-dependent probe amplification.

Bioinformatics and human identification in mass fatality incidents: the world trade center disaster.

Victim identification initiatives undertaken in the wake of Mass Fatality Incidents (MFIs) where high-body fragmentation has been sustained are often dependent on DNA typing technologies to complete their mandate. The success of these endeavors is linked to the choice of DNA typing methods and the bioinformatic tools required to make the necessary associations. Several bioinformatic tools were developed to assist with the identification of the victims of the World Trade Center attacks, one of the most complex incidents to date.

Prediction of MLH1 and MSH2 mutations in Lynch syndrome.

Context: Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2.

Objectives: To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients.

Design, Setting, And Participants: Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2.

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer.

Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families.

Many rearrangement mutations in the BRCA1 gene have been identified. It is becoming clear that some of these mutations are prevalent, and therefore their detection is necessary in order for clinical genetic tests to have high sensitivity. Published information on particular rearrangements is frequently limited to a single patient, small groups of patients, or patients of a particular ethnicity.

Single nucleotide polymorphisms in clinical genetic testing: the characterization of the clinical significance of genetic variants and their application in clinical research for BRCA1.

Clinical genetic testing is increasingly employed in the medical management of cancer patients. These tests support a variety of clinical decisions by providing results that indicate risk for future disease, confirmation of diagnoses, and more recently, therapeutic selection and prognosis. Most genetic variation detected during clinical testing involves single nucleotide polymorphisms (SNPs).

A multi-exonic BRCA1 deletion identified in multiple families through single nucleotide polymorphism haplotype pair analysis and gene amplification with widely dispersed primer sets.

The identification of intragenic rearrangements is important for a comprehensive understanding of mutations that occur in some clinically important genes. Single nucleotide polymorphism haplotypes obtained from clinical sequence data have been used to identify patients at high risk for rearrangement mutations. Application of this method identified a novel 26-kb deletion of BRCA1 exons 14 through 20 in patients from multiple families with hereditary breast and ovarian cancer.

Two rare novel polymorphisms in the D8S1179 and D13S317 markers and method to mitigate their impact on human identification.

Aim: Two rare polymorphisms were identified at the primer annealing sites of the short tandem repeat (STR) loci D8S1179 and D13S317 for a commercial multiplex STR system commonly used for human identification. These polymorphisms resulted in weak amplification from the affected alleles. Therefore, alternative polymerase chain reaction (PCR) thermal cycling conditions were developed that promoted more even signal amplitudes from these alleles by employing reduced annealing temperatures.

Accurate STR allele designations at the FGA and vWA loci despite primer site polymorphisms.

Polymerase chain reaction (PCR)-based STR DNA typing systems are used extensively in the field of human identification. Under optimal PCR conditions, the amplicon yield from both alleles of an STR locus is expected to be approximately equivalent. However, it is reasonable to expect that rare genomic sequence polymorphisms will co-localize with well-designed primer sets and induce allele imbalance or "dropouts".

A biochemical analysis demonstrates that the BRCA1 intronic variant IVS10-2A--> C is a mutation.

Sequence analysis of cDNA from an asymptomatic patient belonging to a high-risk breast cancer family carrying the genetic variant BRCA1 IVS10-2A-->C revealed that functional BRCA1 mRNA was derived from only one of the patient's chromosomes. The other chromosome produced an aberrant RNA splicing transcript that deleted exon 11. Analysis of the patient's genomic DNA demonstrated that the chromosome producing the non-functional mRNA carried the genotype BRCA1 IVS10-2A-->C.