生活習慣病とgenome-wide association study

The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.

mTOR at the nexus of nutrition, growth, ageing and disease

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

/pdf/guidelines-for-investigating-causality-of-sequence-variants-2g9b1oifax.pdf

Guidelines for investigating causality of sequence variants in human disease

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.

/pdf/prevalence-and-architecture-of-de-novo-mutations-in-256ilqyi82.pdf

Prevalence and architecture of de novo mutations in developmental disorders

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.

Genome sequencing identifies major causes of severe intellectual disability

Summary of Clinical Attributes of 4 Infants Who Developed SDH During Treatment With EnoxaparinCase NumberAge of Initiation of LMWHReason for Anticoagulation Age at Finding of SDHSDH Characteristics [Associated Symptoms]Comorbid Brain Injury Neurosurgical InterventionFollow-up Imaging Neurologic Follow-up1 1 wk Right transverse CVST 2.5 mo BilateralSDH,2.7–3.5cmthick, with 8 cm craniocaudal extension and with mass effect [incidentalﬁnding]Severe cystic encephalomalacia and laminar necrosis from unknown causeYes RepeatMRIat2and6moafter bleed,with improvementin size of SDH.Severely impaired, treatment-resistant epilepsy at 12 mo of age.2 11 wk Right transverse and superior sagittal CVST4 mo ExtensivebilateralSDH,1.3cm thick [incidentalﬁnding]Severe brain atrophy, probably from metabolic injury due to severe hypernatremiaYes Cranial ultrasound 3 d after bleed. MRIs at 4 and 8 mo after bleed with improvementinsizeofSDH.Severely impaired, controlled epilepsy at 9 mo of age.3 3 wk Catheter-associated right internal jugular venous thrombus2.5 mo Focal left frontal/parietal SDH, 4.532.735.3 cm, with mild mass effect [caused focal statusepilepticus]Brainatrophy,probablyfroma genetic causeNo Cranial ultrasounds at 4 and 11 d after bleed, head CT scan 6 d after bleed and MRI 3 mo after bleed with mildimprovementinsizeof SDH.Severely impaired. Death at 7 mo of age from respiratory failure after transition to comfort care.4 1 wk Righttransverseandsuperior sagittal CVST3 mo Small focal left parietal SDH, 0.3 cm thick, without mass effect [incidentalnding]Extensive cystic encephalomalacia from hypoxic ischemic injuryNo HeadCTscan1moafterbleed and MRI 10 mo after bleed without evidence of SDH.Severely impaired at 12 mo of age.

With Cerebral Atrophy Subdural Hemorrhages Associated With Antithrombotic Therapy in Infants

Transition of Care in Adolescents with Epilepsy: Perspective of Pediatric Neurologists in India

Transition of Care in Epilepsy.

Non-Epileptic Paroxysmal Events of Childhood

Both adults and children with epilepsy are at high risk for poor bone health, with associated osteopenia and fractures. Epilepsy has consistently been associated with low vitamin D levels, a key indicator of bone health. Many anticonvulsant medications, such as phenytoin and carbamazepine, induce hepatic CYP450 enzymes, resulting in accelerated vitamin D metabolism. This might be the mechanism by which some epilepsy treatments decrease vitamin D levels. However, even medications which result in less-potent CYP450 induction (e.g. oxcarbazepine), or inhibit hepatic enzymes (e.g. valproate), have been associated with abnormal vitamin D levels and poor bone health. Data are lacking for many of the newer anticonvulsant medications. Although vitamin D is only one among many risk factors for abnormal bone mineral density, it is a modifiable risk factor for people with epilepsy. We suggest guidelines for screening and treatment of vitamin D insufficiency for people with epilepsy.

Sucheta M. Joshi

Papers

With Cerebral Atrophy Subdural Hemorrhages Associated With Antithrombotic Therapy in Infants

Transition of Care in Adolescents with Epilepsy: Perspective of Pediatric Neurologists in India

Transition of Care in Epilepsy.

Non-Epileptic Paroxysmal Events of Childhood

Vitamin D and bone health among people with epilepsy