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1.  Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes 
Molecular Psychiatry  2009;15(6):637-646.
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.
PMCID: PMC2877197  PMID: 19546859
CNV; ADHD; GRM5; GRM7; PTPRD; autism; schizophrenia
2.  MLPA: A Rapid, Reliable, and Sensitive Method for Detection and Analysis of Abnormalities of 22q 
Human mutation  2006;27(8):814.
In this study, essential test characteristics of the recently described multiplex ligation-dependent probe amplification (MLPA) method are presented, using chromosome 22 as a model. This novel method allows the relative quantification of ~40–45 different target DNA sequences in a single reaction. For the purpose of this study, MLPA was performed in a blinded manner on a training set containing over 50 samples, including typical 22q11.2 deletions, various atypical deletions, duplications (trisomy and tetrasomy), and unbalanced translocations. All samples in the training set have been previously characterized by fluorescence in situ hybridization (FISH) with cosmid or BAC clones and/or cytogenetic studies. MLPA findings were consistent with cytogenetic and FISH studies, no rearrangement went undetected and repeated tests gave consistent results. At a relative change in comparative signal strength of 30% or more, sensitivity and specificity values were 0.95 and 0.99, respectively. Given that MLPA is likely to be used as an initial screening method, a higher sensitivity, at the cost of a lower specificity, was deemed more appropriate. A receiver operator characteristic (ROC) curve analysis was performed to calculate the most optimal threshold range, with associated sensitivity and specificity values of 0.99 and 0.97, respectively. Finally, performance of each individual probe was analyzed, providing further useful information for the interpretation of MLPA results. In conclusion, MLPA has proven to be a highly sensitive and accurate tool for detecting copy number changes in the 22q11.2 region, making it a fast and economic alternative to currently used methods. The current study provides valuable and detailed information on the characteristics of this novel method.
PMCID: PMC2814414  PMID: 16791841
MLPA; atypical rearrangements; velocardiofacial syndrome; VCFS; DiGeorge; conotruncal anomaly; 22q11DS
4.  Heritable breast cancer in twins 
British Journal of Cancer  2002;87(3):294-300.
Known major mutations such as BRCA1/2 and TP53 only cause a small proportion of heritable breast cancers. Co-dominant genes of lower penetrance that regulate hormones have been thought responsible for most others. Incident breast cancer cases in the identical (monozygotic) twins of representative cases reflect the entire range of pertinent alleles, whether acting singly or in combination. Having reported the rate in twins and other relatives of cases to be high and nearly constant over age, we now examine the descriptive and histological characteristics of the concordant and discordant breast cancers occurring in 2310 affected pairs of monozygotic and fraternal (dizygotic) twins in relation to conventional expectations and hypotheses. Like other first-degree relatives, dizygotic co-twins of breast cancer cases are at higher than usual risk (standardised incidence ratio (SIR)=1.7, CI=1.1–2.6), but the additional cases among monozygotic co-twins of cases are much more numerous, both before and after menopause (SIR=4.4, CI=3.6–5.6), than the 100% genetic identity would predict. Monozygotic co-twin diagnoses following early proband cancers also occur more rapidly than expected (within 5 years, SIR=20.0, CI=7.5–53.3). Cases in concordant pairs represent heritable disease and are significantly more likely to be oestrogen receptor-positive than those of comparable age from discordant pairs. The increase in risk to the monozygotic co-twins of cases cannot be attributed to the common environment, to factors that cumulate with age, or to any aggregate of single autosomal dominant mutations. The genotype more plausibly consists of multiple co-existing susceptibility alleles acting through heightened susceptibility to hormones and/or defective tumour suppression. The resultant class of disease accounts for a larger proportion of all breast cancers than previously thought, with a rather high overall penetrance. Some of the biological characteristics differ from those of breast cancer generally.
British Journal of Cancer (2002) 87, 294–300. doi:10.1038/sj.bjc.6600429
© 2002 Cancer Research UK
PMCID: PMC2364223  PMID: 12177798
breast neoplasms; genetics; etiology; pathogenesis; twins
5.  Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function 
Thorax  2000;55(4):271-276.
BACKGROUND—Exposure to environmental tobacco smoke (ETS) during childhood and in utero exposure to maternal smoking are associated with adverse effects on lung growth and development.
METHODS—A study was undertaken of the associations between maternal smoking during pregnancy, exposure to ETS, and pulmonary function in 3357 school children residing in 12 Southern California communities. Current and past exposure to household ETS and exposure to maternal smoking in utero were assessed by a self-administered questionnaire completed by parents of 4th, 7th, and 10th grade students in 1993.Standard linear regression techniques were used to estimate the effects of in utero and ETS exposure on lung function, adjusting for age, sex, race, Hispanic ethnicity, height, weight, asthma, personal smoking, and selected household characteristics.
RESULTS—In utero exposure to maternal smoking was associated with reduced peak expiratory flow rate (PEFR) (-3.0%, 95% CI -4.4 to -1.4), mean mid expiratory flow (MMEF) (-4.6%, 95% CI -7.0 to -2.3), and forced expiratory flow (FEF75) (-6.2%, 95% CI -9.1 to -3.1), but not forced expiratory volume in one second (FEV1). Adjusting for household ETS exposure did not substantially change these estimates. The reductions in flows associated with in utero exposure did not significantly vary with sex, race, grade, income, parental education, or personal smoking. Exposure to two or more current household smokers was associated with reduced MMEF (-4.1%, 95% CI -7.6 to -0.4) and FEF75 (-4.4%, 95% CI -9.0 to 0.4). Current or past maternal smoking was associated with reductions in PEFR and MMEF; however, after adjustment for in utero exposure, deficits in MMEF and FEF75 associated with all measurements of ETS were substantially reduced and were not statistically significant.
CONCLUSIONS—In utero exposure to maternal smoking is independently associated with decreased lung function in children of school age, especially for small airway flows.

PMCID: PMC1745733  PMID: 10722765
6.  Effect of spirometer temperature on FEV1 in a longitudinal epidemiological study 
OBJECTIVES: To assess the magnitude of error in pulmonary function measurements introduced by variation in spirometer temperature under field conditions. In a large scale epidemiological study of school children, the influence was investigated of spirometer temperature on forced expiratory volume in 1 second (FEV1) measured with dry rolling seal volumetric spirometers and conventional body temperature, pressure, and saturation (BTPS) corrections. METHODS: Linear regression analyses were performed on data from 995 test-retest pairs on 851 different children, with 1-110 days between test and retest, and spirometer temperature differences between -13 degrees C and +9 degrees C. RESULTS: After adjusting for effects of growth (test-retest intervals) and circadian variation (changes in times of testing), differences in standard BTPS corrected FEV1 showed significant (p < 0.05) dependence on differences in spirometer temperature between tests (-0.24%/degree C). CONCLUSIONS: When spirometer temperatures vary widely, standard BTPS correction does not fully adjust for gas contraction. To improve accuracy of volume measurements in epidemiological studies, additional correction for variation in spirometer temperature should be considered.
PMCID: PMC1757668  PMID: 10658554
7.  Genetic diversity in human Fc receptor II for immunoglobulin G: Fc gamma receptor IIA ligand-binding polymorphism. 
Fc gamma receptors, and in particular genetic variation in these receptors, are important in disorders of hose defense, immunohematologic disease, and systemic autoimmune diseases. We investigated the His-Arg (CAT/CGT) polymorphism at codon 131 of the Fc gamma receptor IIA gene, which influences ligand binding by the receptor. Previously, individuals had been classified phenotypically on the basis of differential binding of murine immunoglobulin G1, but the Fc gamma receptor IIA genotype distribution has not been reported. We used selective PCR-based sequence analysis of genomic DNA to determine the distribution in healthy individuals. For African-Americans, the genotype distribution was determined to be A/A (14%), A/G (60%), and G/G (26%); for Caucasian Americans, the distribution was A/A (30%), A/G (51%), and G/G (19%). These data correlate well with phenotypic data. We implemented a nonradioactive single-stranded conformational polymorphism analysis to rapidly identify all three genotypes. The PCR-single-stranded conformational polymorphism analysis method will facilitate studies of the genotype distribution in individuals with disorders of immune function.
PMCID: PMC368380  PMID: 8556514
9.  A large deletion encompassing the entire alpha-like globin gene cluster in a family of northern European extraction. 
Nucleic Acids Research  1988;16(23):11223-11235.
We describe a new deletional form of alpha thalassemia segregating in three generations of a family of northern European origin. A full-term female girl had hypochromic, microcytic anemia since early infancy associated with delayed language development, slow growth and weight gain. Hematologic studies suggested the presence of alpha thalassemia. Gene-blotting studies showed no abnormal alpha-like globin gene fragments; however, studies of inheritance of informative polymorphic restriction fragments using zeta, alpha and 3'-alpha-hypervariable region (3'-HVR) probes showed evidence for an extensive deletion encompassing the entire alpha-like globin gene cluster. The 3' breakpoint of this deletion maps beyond the 3'-HVR, a region implicated as a hot spot for the generation of other large deletional events within the alpha-like cluster. The 5' breakpoint maps at least 10 kilobases (kb) 5' to the zeta-globin gene. The minimum size estimate for this deletion is greater than 47 kilobases.
PMCID: PMC339006  PMID: 2905048

Results 1-11 (11)