Dorothy Warburton

Bio: Dorothy Warburton is an academic researcher from Columbia University. The author has contributed to research in topics: Trisomy & Abortion. The author has an hindex of 59, co-authored 187 publications receiving 13932 citations. Previous affiliations of Dorothy Warburton include University of Connecticut & University of York.

Strong Association of De Novo Copy Number Mutations with Autism

Abstract: We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

De novo mutations in histone-modifying genes in congenital heart disease

Abstract: Exome sequencing of patients with congenital heart disease (CHD) and their unaffected parents reveals an excess of strong-effect, protein-altering de novo mutations in genes expressed in the developing heart, many of which regulate chromatin modification in key developmental genes; collectively, these mutations are predicted to account for approximately 10% of severe CHD cases. This paper demonstrates that de novo mutations with large effect have a role in the pathogenesis of at least 10% of cases of congenital heart disease (CHD). Using exome sequence analysis in parent–offspring trios Richard Lifton and colleagues compared the frequency of de novo mutations, identified by exome sequencing, in 362 CHD parent–offspring trios and 264 control trios. Gene ontology analysis demonstrated significant enrichment of de novo protein-altering mutation of genes involved in chromatin modification, notably a marked enrichment of genes involved in the production, removal and reading of methylation of histone H3K4 and H3K27. Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation2,3,4. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer5. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints.

Abstract: A questionnaire sent to major cytogenetics laboratories in the United States and Canada over a 10-year period collected data on the frequency and outcome of cases with either apparently balanced de novo rearrangements or de novo supernumerary marker chromosomes detected at amniocentesis. Of 377,357 reported amniocenteses, approximately 1/2,000 had a de novo reciprocal translocation, 1/9,000 a Robertsonian translocation, 1/10,000 a de novo inversion, and 1/2,500 an extra structurally abnormal chromosome of unidentifiable origin. The risk of a serious congenital anomaly was estimated to be 6.1% (n = 163) for de novo reciprocal translocations, 3.7% (n = 51) for Robertsonian translocations, and 9.4% (n = 32) for inversions. The combined risk for reciprocal translocations and inversions was 6.7% (95% confidence limits 3.1%-10.3%). The risk of abnormality for extra nonsatellited marker chromosomes was 14.7% (n = 68), and that for satellited marker chromosomes was 10.9% (n = 55). In non-Robertsonian rearrangements, distribution of breakpoints among chromosomes was not as would be expected strictly on the basis of length. Most breaks were stated to occur within G-negative bands, but there was little evidence of particular hot spots among these bands. Nevertheless, there did appear to be a correlation between those bands in which breakage was observed most often and those bands where common or rare fragile sites have been described.

Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired.

Abstract: Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region1 lies between markers D13S136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs2. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism

Abstract: The proportions of chromosomal genotypes associated with the Turner syndrome genotype (excluding those with a Y chromosome) in embryonic and fetal deaths, in fetuses diagnosed prenatally, and in living individuals were reviewed. The ratio of apparent non-mosaic 45,X to 45,X/46,XX mosaics was notably higher in a New York City series of embryonic and fetal deaths, 13.5 to 1, than in living individuals reported to the New York State Chromosome Registry, 3.6 to 1. The ratios of 45,X cases to those with 46,Xi(Xq) was 5.7 to 1 in living individuals, but was 112 to 0 in embryonic and fetal deaths, an even greater disparity, indicating the marked fetoprotective effect of more than one dose of some locus or loci on the long arm of the X chromosome. The results of review of data pertinent to the livebirth prevalence of the (apparent non-mosaic) 45,X geno-type suggest a rate of about 5.7 per 100,000 livebirths (11.8 per 100,000 females) with 95% confidence limits of 2.6 per 100,000 to 10.8 per 100,000. The rate in fetuses diagnosed prenatally is 8/27,202, about 30 per 100,000. As a large proportion of these, perhaps 75%, would undergo spontaneous fetal death if not terminated electively, these figures are consistent with the direct estimate of livebirth rates. The rate of all those with X chromosome abnormalities (without a Y chromosome) associated with signs or symptoms that eventually lead to referral for cytogenetic study was estimated at a minimum of 10.7 per 100,000 livebirths, (22.2 per 100,000 females).

Finding the missing heritability of complex diseases

Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association

Abstract: March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Benjamin, MD, ScM, FAHA, Chair Paul Muntner, PhD, MHS, FAHA, Vice Chair Alvaro Alonso, MD, PhD, FAHA Marcio S. Bittencourt, MD, PhD, MPH Clifton W. Callaway, MD, FAHA April P. Carson, PhD, MSPH, FAHA Alanna M. Chamberlain, PhD Alexander R. Chang, MD, MS Susan Cheng, MD, MMSc, MPH, FAHA Sandeep R. Das, MD, MPH, MBA, FAHA Francesca N. Delling, MD, MPH Luc Djousse, MD, ScD, MPH Mitchell S.V. Elkind, MD, MS, FAHA Jane F. Ferguson, PhD, FAHA Myriam Fornage, PhD, FAHA Lori Chaffin Jordan, MD, PhD, FAHA Sadiya S. Khan, MD, MSc Brett M. Kissela, MD, MS Kristen L. Knutson, PhD Tak W. Kwan, MD, FAHA Daniel T. Lackland, DrPH, FAHA Tené T. Lewis, PhD Judith H. Lichtman, PhD, MPH, FAHA Chris T. Longenecker, MD Matthew Shane Loop, PhD Pamela L. Lutsey, PhD, MPH, FAHA Seth S. Martin, MD, MHS, FAHA Kunihiro Matsushita, MD, PhD, FAHA Andrew E. Moran, MD, MPH, FAHA Michael E. Mussolino, PhD, FAHA Martin O’Flaherty, MD, MSc, PhD Ambarish Pandey, MD, MSCS Amanda M. Perak, MD, MS Wayne D. Rosamond, PhD, MS, FAHA Gregory A. Roth, MD, MPH, FAHA Uchechukwu K.A. Sampson, MD, MBA, MPH, FAHA Gary M. Satou, MD, FAHA Emily B. Schroeder, MD, PhD, FAHA Svati H. Shah, MD, MHS, FAHA Nicole L. Spartano, PhD Andrew Stokes, PhD David L. Tirschwell, MD, MS, MSc, FAHA Connie W. Tsao, MD, MPH, Vice Chair Elect Mintu P. Turakhia, MD, MAS, FAHA Lisa B. VanWagner, MD, MSc, FAST John T. Wilkins, MD, MS, FAHA Sally S. Wong, PhD, RD, CDN, FAHA Salim S. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee

Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association.

Abstract: Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association

Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...