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In this article, we study the effects of prenatal health on educational attainment and on the reproduction of family background inequalities in education. Using Finnish birth cohort data, we analyze several maternal and fetal health variables, many of which have not been featured in the literature on long-term socioeconomic effects of health despite the effects of these variables on birth and short-term health outcomes. We find strong negative effects of mother's prenatal smoking on educational attainment, which are stronger if the mother smoked heavily but are not significant if she quit during the first trimester. Anemia during pregnancy is also associated with lower levels of attained education. Other indicators of prenatal health (pre-pregnancy obesity, mother's antenatal depressed mood, hypertension and preeclampsia, early prenatal care visits, premature birth, and small size for gestational age) do not predict educational attainment. Our measures explain little of the educational inequalities by parents' class or education. However, smoking explains 12%—and all health variables together, 19%—of the lower educational attainment of children born to unmarried mothers. Our findings point to the usefulness of proximate health measures in addition to general ones. They also point to the potentially important role played by early health in intergenerational processes.

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1 E17K , a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions 1 . Lissencephaly (‘smooth brain’) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability 2 . However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 ( PIDD1 ) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders. Cellular, transcriptomic and proteomic analyses of organoids derived from human induced pluripotent stem cells show that mTOR pathway hypoactivation is involved in two genetically distinct lissencephaly spectrum disorders.

Objective: To examine the number of cases filed about Down syndrome in terms of its numbers, causes and consequences, to provide an overview of what doctors should pay attention to when informing and consulting patients and during follow-up and recommend solutions for decreasing the number of malpractice cases. (Discussing the legal aspect of the decisions is beyond the scope of this research.)Materials and Methods: ‘Down’, ‘Down sendromu’ ‘Down’s, ‘trizomi 21 ‘, ‘trisomi 21’ and ‘trisomy 21’ was written to ‘ https://karararama.yargitay.gov.tr/ ‘ and ‘https://karararama.danistay.gov.tr/’ web addresses search engines and the data was examined with Microsoft Excel or with R version 4.0.5 ( 2021-03-31) for bias and frequency table was used and the results were examined.Results: A total of 53 cases were found. 49 supreme court and 4 Council of State court decisions are found. The cases are from 27.10.2009 to 13.10.2021.Conclusion: A total of 39 different Down syndrome cases were examined, as 6 of the 53 cases were related to the same cases and 8 of them were cases not related to Down syndrome. 28 cases are “doctor negligence”, 5 are “reckless killing”, 1 “material mixing in the genetic center”, 1 “unauthorized use of the child’s photo”, 1 “stealing money from the child”, 1 “intentionally injuring the child”, 1 ‘inheritance request for the child’ and 1 on ‘guardianship’.

Gene linked to brain malformation The identification of genetic loci linked to abnormal cortical development is complicated by genetic heterogeneity, small family sizes and diagnostic classifications that do not reflect molecular pathogenesis. These obstacles have been overcome in a study using whole-exome sequencing. Recessive mutations in the WD repeat domain 62 ( WDR62 ) gene are shown to cause a wide spectrum of seemingly disparate brain abnormalities, including microcephaly, pachygyria and, in one instance, cerebellar hypoplasia. Unlike other known microcephaly genes, WDR62 does not associate with centrosomes; it is predominantly nuclear in localization and is expressed transiently in the neocortex during embryonic neurogenesis. Mapping disease loci that underlie putative Mendelian forms of malformations of cortical development is complicated by genetic heterogeneity, small family sizes and diagnostic classifications that may not reflect molecular pathogenesis. These authors use whole-exome sequencing to identify recessive mutations in WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations. WDR62 's nuclear localization to germinal neuroepithelia indicates that cortical malformations can be caused by events during progenitor proliferation and neurogenesis. The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers 1 , 2 . An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development 3 , 4 , 5 , 6 . Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 ( WDR62 ) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2 , encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities 1 . Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons. Biallelic truncating mutations in CTNNA2 , encoding αN-catenin, cause a new pachygyria syndrome associated with actin regulation and ARP2 and ARP3 repression in neurons.