9 research outputs found
Prevalence and architecture of de novo mutations in developmental disorders.
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)
High-fiber diet in HIV-positive men is associated with lower risk of developing fat deposition
Effect of a dietary intervention and n−3 fatty acid supplementation on measures of serum lipid and insulin sensitivity in persons with HIV123
Background: Elevated serum triglyceride and low HDL-cholesterol concentrations have been reported in persons with HIV
Micronutrient concentrations and subclinical atherosclerosis in adults with HIV123
Background: Extremes in micronutrient intakes are common in HIV-infected patients in developed countries and may affect the progression of atherosclerosis in this population
Metabolic syndrome and serum fatty acid patterns in serum phospholipids in hypertriglyceridemic persons with human immunodeficiency virus123
Background: HIV infection and its treatment are associated with abnormal lipid profiles. High triglyceride concentrations and low HDL-cholesterol concentrations are the most common health abnormalities and raise concerns about an increased risk of cardiovascular disease
Fertility and development: the roles of schooling and family production
This paper presents a quantitative theory of development that highlights three mechanisms that relate schooling, fertility, and growth. First, we point out that in the early stages of development, fertility and schooling may rise together as the schooling of younger children increases their relative contribution to family income when they turn working age. Second, the model contains a supply-side theory of schooling that generates a rise in schooling independent of technological change. Third, we introduce a direct negative effect of industrialization on fertility that does not operate through human capital and the quantity-quality tradeoff. An initial quantitative assessment of the theoretical mechanisms is conducted by calibrating and applying the model to United States history from 1800 to 2000. We find that the demise in family production is an important factor reducing fertility in the 19th century and schooling of older children is dominant factor reducing fertility in the 20th century. The same model is applied to England from 1740 to 1940, where we offer two complimentary explanations for the rise in fertility from 1740 to 1820. The first is based on the rapid expansion in the cottage industry and the second on the increased relative productivity of children. We also find that the subsequent fall in fertility from 1820 to 1940 cannot be explained without introducing child labor/compulsory schooling laws. Copyright Springer Science+Business Media, LLC 2006Economic development, Fertility, Schooling, Family production,
Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article