Laura Arbour

Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects

Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A-->G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28-5.13) for being a case and of 3.05 (95% CI 1.54-6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49-72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84-12.85). We propose that the genetic-nutrient interaction--MTHFR polymorphism and low folate status--is associated with a greater risk for NTDs than either variable alone.

Oligonucleotide Microarray Analysis of Genomic Imbalance in Children with Mental Retardation

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.

Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

Submicroscopic deletions and duplications in individuals with intellectual disability detected by array‐CGH

Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35–49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50–70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5–10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome‐wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a ∼15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004 ; Lapierre et al., 2004 ; Schoumans et al., 2004 ; Vermeesch et al., 2005 ] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3‐13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3‐13.1, Xp22.3 is provided.

Race and ancestry in biomedical research: exploring the challenges.

The use of race in biomedical research has, for decades, been a source of social controversy. However, recent events, such as the adoption of racially targeted pharmaceuticals, have raised the profile of the race issue. In addition, we are entering an era in which genomic research is increasingly focused on the nature and extent of human genetic variation, often examined by population, which leads to heightened potential for misunderstandings or misuse of terms concerning genetic variation and race. Here, we draw together the perspectives of participants in a recent interdisciplinary workshop on ancestry and health in medicine in order to explore the use of race in research issue from the vantage point of a variety of disciplines. We review the nature of the race controversy in the context of biomedical research and highlight several challenges to policy action, including restrictions resulting from commercial or regulatory considerations, the difficulty in presenting precise terminology in the media, and drifting or ambiguous definitions of key terms.

DNA on Loan: Issues to Consider when Carrying Out Genetic Research with Aboriginal Families and Communities

In the current research milieu where genetic etiology is considered a critical component in the discovery of pathogenesis, aboriginal families and communities affected with genetic conditions may be considered as research participants. However, because of concerns about the impact of genetic information and historical harmful research practices, some aboriginal communities have considerable unease when faced with this prospect. Therefore, in the circumstance that genetics is considered an important part of research inquiry by aboriginal families and communities, there needs to be assurance that the research will be carried out according to mutual expectations. A research relationship that respects aboriginal individuals and communities within their culture and is in keeping with their values is essential. This respect extends to the use of biological samples, considering the DNA to be ‘on loan’ to the researcher for the purpose of the research for which consent was obtained. This paper will explore practical ways of maintaining a respectful research relationship when genetics research with aboriginal people is undertaken.

The Gene for Juvenile Hyaline Fibromatosis Maps to Chromosome 4q21

Juvenile hyaline fibromatosis (JHF) is an autosomal recessive condition characterized by multiple subcutaneous nodular tumors, gingival fibromatosis, flexion contractures of the joints, and an accumulation of hyaline in the dermis. We performed a genomewide linkage search in two families with JHF from the same region of the Indian state of Gujarat and identified a region of homozygosity on chromosome 4q21. Dense microsatellite analyses within this interval in five families with JHF who were from diverse origins demonstrate that all are compatible with linkage to chromosome 4q21 (multipoint LOD score 5.5). Meiotic recombinants place the gene for JHF within a 7-cM interval bounded by D4S2393 and D4S395.

Heavy smoking during pregnancy as a marker for other risk factors of adverse birth outcomes: a population-based study in British Columbia, Canada

BackgroundSmoking during pregnancy is associated with known adverse perinatal and obstetrical outcomes as well as with socio-economic, demographic and other behavioural risk factors that independently influence outcomes. Using a large population-based perinatal registry, we assess the quantity of cigarettes smoked for the magnitude of adverse birth outcomes and also the association of other socio-economic and behavioural risk factors documented within the registry that influence pregnancy outcomes. Our goal was to determine whether number of cigarettes smoked could identify those in greatest need for comprehensive intervention programs to improve outcomes.MethodsOur population-based retrospective study of singleton births from 2001 to 2006 (N = 237,470) utilized data obtained from the BC Perinatal Database Registry. Smoking data, self reported at the earliest prenatal visit, was categorized as: never, former, light (1 to 4), moderate (5 to 9), or heavy smoker (10 or more per day). Crude and adjusted odds ratios (AOR) with 95% confidence intervals (95% CI) were calculated using logistic regression models for smoking frequency and adverse birth outcomes. A partial proportional odds (pp-odds) model was used to determine the association between smoking status and other risk factors.ResultsThere were 233,891 singleton births with available smoking status data. A significant dose-dependent increase in risk was observed for the adverse birth outcomes small-for-gestational age, term low birth weight and intra-uterine growth restriction. Results from the pp-odds model indicate heavy smokers were more likely to have not graduated high school: AOR (95% CI) = 3.80 (3.41-4.25); be a single parent: 2.27 (2.14-2.42); have indication of drug or alcohol use: 7.65 (6.99-8.39) and 2.20 (1.88-2.59) respectively, attend fewer than 4 prenatal care visits: 1.39 (1.23-1.58), and be multiparous: 1.59 (1.51-1.68) compared to light, moderate and non-smokers combined.ConclusionOur data suggests that self reports of heavy smoking early in pregnancy could be used as a marker for lifestyle risk factors that in combination with smoking influence birth outcomes. This information may be used for planning targeted intervention programs for not only smoking cessation, but potentially other support services such as nutrition and healthy pregnancy education.

Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1

A susceptibility gene for Wilms’ tumour (WT), designated FWT1, was previously mapped to chromosome 17q12–q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT.

Glutathione deficiency as a complication of methylmalonic acidemia: Response to high doses of ascorbate

A 7-year-old boy with deficient activity of methylmalonyl coenzyme A mutase (mut-methylmalonic acidemia) was seen in severe metabolic crisis. After hemodialysis and clearance of toxic metabolites, severe lactic acidosis persisted with multiorgan failure. Glutathione deficiency was noted and high-dose ascorbate therapy (120 mg/kg) commenced. Glutathione deficiency may contribute to the lactic acidosis observed during decompensation in patients with methylmalonic acidemia.