Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

BackgroundThe causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.MethodsRetrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.ResultsBetween 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).ConclusionsMolecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence

Wormwholes: A Commentary On K.F. Schaffer\u27s Genes, Behavior, And Developmental Emergentism

Although Caenorhabditis elegans was chosen and modified to be an organism that would facilitate a reductionist program for neurogenetics, recent research has provided evidence for properties that are emergent from the neurons. While neurogenetic advances have been made using C. elegans which may be useful in explaining human neurobiology, there are severe limitations on C. elegans to explain any significant human behavior

Innovative approaches to the study of social phenotypes in neurodevelopmental disorders: an introduction to the research topic

R01 HD033470 - NICHD NIH HH

Multiparameter behavioral profiling reveals distinct thermal response regimes in Caenorhabditis elegans.

BackgroundResponding to noxious stimuli by invoking an appropriate escape response is critical for survival of an organism. The sensations of small and large changes in temperature in most organisms have been studied separately in the context of thermotaxis and nociception, respectively. Here we use the nematode C. elegans to address the neurogenetic basis of responses to thermal stimuli over a broad range of intensities.ResultsC. elegans responds to aversive temperature by eliciting a stereotypical behavioral sequence. Upon sensation of the noxious stimulus, it moves backwards, turns and resumes forward movement in a new direction. In order to study the response of C. elegans to a broad range of noxious thermal stimuli, we developed a novel assay that allows simultaneous characterization of multiple aspects of escape behavior elicited by thermal pulses of increasing amplitudes. We exposed the laboratory strain N2, as well as 47 strains with defects in various aspects of nervous system function, to thermal pulses ranging from ΔT = 0.4°C to 9.1°C and recorded the resulting behavioral profiles.ConclusionsThrough analysis of the multidimensional behavioral profiles, we found that the combinations of molecules shaping avoidance responses to a given thermal pulse are unique. At different intensities of aversive thermal stimuli, these distinct combinations of molecules converge onto qualitatively similar stereotyped behavioral sequences

The Three Neurogenetic Phases of Human Consciousness

This paper is an organization and conceptualization of a genetic account of human consciousness and to establish an initial list of the neurogenetic correlates of consciousness (NgCC). This will be accomplished by establishing networks of genes that are involved in the multiple facets of the process of human consciousness. The methodology utilized in this work is the evaluation of a small number of genes that have been researched experimentally in order to understand their role in brain development and function. The results demonstrate that most neurogenetic genes can be categorized into three phases: the emergence of neuron-based consciousness, the continuum of neuron-based consciousness, and the neurodegeneration of consciousness. This work also revealed that some genes have a function in more than one of the neurogenetic phases. As of now a starting point has been established in terms of identifying some NgCC but there is room for expansion as there are likely to be hundreds of more genes that have yet to be identified or the function pertaining to human consciousness has not yet been fully understood

Stem cells and the origin of gliomas: A historical reappraisal with molecular advancements.

The biology of both normal and tumor development clearly possesses overlapping and parallel features. Oncogenes and tumor suppressors are relevant not only in tumor biology, but also in physiological developmental regulators of growth and differentiation. Conversely, genes identified as regulators of developmental biology are relevant to tumor biology. This is particularly relevant in the context of brain tumors, where recent evidence is mounting that the origin of brain tumors, specifically gliomas, may represent dysfunctional developmental neurobiology. Neural stem cells are increasingly being investigated as the cell type that originally undergoes malignant transformation - the cell of origin - and the evidence for this is discussed

Neural, Genetic, And Neurogenetic Approaches For Solving The 0-1 Multidimensional Knapsack Problem

The multi-dimensional knapsack problem (MDKP) is a well-studied problem in Decision Sciences. The problem’s NP-Hard nature prevents the successful application of exact procedures such as branch and bound, implicit enumeration and dynamic programming for larger problems. As a result, various approximate solution approaches, such as the relaxation approaches, heuristic and metaheuristic approaches have been developed and applied effectively to this problem. In this study, we propose a Neural approach, a Genetic Algorithms approach and a Neurogenetic approach, which is a hybrid of the Neural and the Genetic Algorithms approach. The Neural approach is essentially a problem-space based non-deterministic local-search algorithm. In the Genetic Algorithms approach we propose a new way of generating initial population. In the Neurogenetic approach, we show that the Neural and Genetic iterations, when interleaved appropriately, can complement each other and provide better solutions than either the Neural or the Genetic approach alone. Within the overall search, the Genetic approach provides diversification while the Neural provides intensification. We demonstrate the effectiveness of our proposed approaches through an empirical study performed on several sets of benchmark problems commonly used in the literature

The Task Scheduling Problem: A NeuroGenetic Approach

This paper addresses the task scheduling problem which involves minimizing the makespan in scheduling n tasks on m machines (resources) where the tasks follow a precedence relation and preemption is not allowed.  The machines (resources) are all identical and a task needs only one machine for processing.  Like most scheduling problems, this one is NP-hard in nature, making it difficult to find exact solutions for larger problems in reasonable computational time.  Heuristic and metaheuristic approaches are therefore needed to solve this type of problem.   This paper proposes a metaheuristic approach - called NeuroGenetic - which is a combination of an augmented neural network and a genetic algorithm.  The augmented neural network approach is itself a hybrid of a heuristic approach and a neural network approach.  The NeuroGenetic approach is tested against some popular test problems from the literature, and the results indicate that the NeuroGenetic approach performs significantly better than either the augmented neural network or the genetic algorithms alone.