scholarly journals Genetics of neuromuscular fetal akinesia in the genomics era

2018 ◽  
Vol 55 (8) ◽  
pp. 505-514 ◽  
Author(s):  
Sarah Jane Beecroft ◽  
Marcus Lombard ◽  
David Mowat ◽  
Catriona McLean ◽  
Anita Cairns ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Disease Gene ◽  
Genetic Diagnosis ◽  
Recurrence Risk ◽  
Population Based ◽  
Disease Genes ◽  
Neuromuscular System ◽  
Mendelian Genetics ◽  
Planning Decisions ◽  
Disease Gene Discovery

Fetal hypokinesia or akinesia encompasses a broad spectrum of disorders, united by impaired movement in utero. Often, the underlying aetiology is genetic in origin, affecting part of the neuromuscular system. The affordable and high-throughput nature of next-generation DNA sequencing has led to an explosion in disease gene discovery across rare diseases, including fetal akinesias. A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions. More broadly, knowledge of disease genes increasingly allows population-based preconception carrier screening, which has reduced the incidence of recessive diseases in several populations. Despite gains in knowledge of the genetics of fetal akinesia, many families lack a genetic diagnosis. In this review, we describe the developments in Mendelian genetics of neuromuscular fetal akinesia in the genomics era. We examine genetic diagnoses with neuromuscular causes, specifically including the lower motor neuron, peripheral nerve, neuromuscular junction and muscle.

scholarly journals Human and mouse essentiality screens as a resource for disease gene discovery

2019 ◽  
Author(s):  
Pilar Cacheiro ◽  
Violeta Muñoz-Fuentes ◽  
Stephen A. Murray ◽  
Mary E. Dickinson ◽  
Maja Bucan ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Disease Gene ◽  
De Novo ◽  
Genetic Diseases ◽  
Gene Discovery ◽  
Tissue Expression ◽  
Human Cell Line ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Disease Gene Discovery

ABSTRACTAlthough genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing characteristics in the biological processes they regulate, tissue expression levels and human mutation rates. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented in the developmental lethal category, representing genes not essential for cell survival but required for organism development. Exploiting this finding, we have screened developmental disorder cases from three independent disease sequencing consortia and identified potentially pathogenic, de novo variants shared in different patients for several developmental lethal genes that have not previously been associated with rare disease. We therefore propose FUSIL as an efficient resource for disease gene discovery.

scholarly journals A genomic autopsy identifies causes of perinatal death and provides options to prevent recurrence

2022 ◽  
Author(s):  
Hamish Scott ◽  
Alicia Byrne ◽  
Peer Arts ◽  
Thuong Ha ◽  
Karin Kassahn ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Developmental Disorders ◽  
Perinatal Death ◽  
Genetic Diagnosis ◽  
Clinical Importance ◽  
Recurrence Risk ◽  
In Utero ◽  
Disease Genes ◽  
Genomic Disorders

Abstract Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

scholarly journals First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery

2020 ◽  
Vol 28 (8) ◽  
pp. 1034-1043 ◽  
Author(s):  
Holger Hengel ◽  
Rebecca Buchert ◽  
Marc Sturm ◽  
Tobias B. Haack ◽  
Yvonne Schelling ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
Disease Gene ◽  
Gene Discovery ◽  
First Line ◽  
Disease Gene Discovery ◽  
Israeli Arabs

scholarly journals Disease Modeling and Disease Gene Discovery in Cardiomyopathies: A Molecular Study of Induced Pluripotent Stem Cell Generated Cardiomyocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3311
Author(s):  
Satish Kumar ◽  
Joanne E. Curran ◽  
Kashish Kumar ◽  
Erica DeLeon ◽  
Ana C. Leandro ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Disease Gene ◽  
Disease Modeling ◽  
Gene Discovery ◽  
Induced Pluripotent Stem Cell ◽  
P Value ◽  
Disease Gene Discovery ◽  
Induced Pluripotent

The in vitro modeling of cardiac development and cardiomyopathies in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) provides opportunities to aid the discovery of genetic, molecular, and developmental changes that are causal to, or influence, cardiomyopathies and related diseases. To better understand the functional and disease modeling potential of iPSC-differentiated CMs and to provide a proof of principle for large, epidemiological-scale disease gene discovery approaches into cardiomyopathies, well-characterized CMs, generated from validated iPSCs of 12 individuals who belong to four sibships, and one of whom reported a major adverse cardiac event (MACE), were analyzed by genome-wide mRNA sequencing. The generated CMs expressed CM-specific genes and were highly concordant in their total expressed transcriptome across the 12 samples (correlation coefficient at 95% CI =0.92 ± 0.02). The functional annotation and enrichment analysis of the 2116 genes that were significantly upregulated in CMs suggest that generated CMs have a transcriptomic and functional profile of immature atrial-like CMs; however, the CMs-upregulated transcriptome also showed high overlap and significant enrichment in primary cardiomyocyte (p-value = 4.36 × 10−9), primary heart tissue (p-value = 1.37 × 10−41) and cardiomyopathy (p-value = 1.13 × 10−21) associated gene sets. Modeling the effect of MACE in the generated CMs-upregulated transcriptome identified gene expression phenotypes consistent with the predisposition of the MACE-affected sibship to arrhythmia, prothrombotic, and atherosclerosis risk.

scholarly journals MOSES: A New Approach to Integrate Interactome Topology and Functional Features for Disease Gene Prediction

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1713
Author(s):  
Manuela Petti ◽  
Lorenzo Farina ◽  
Federico Francone ◽  
Stefano Lucidi ◽  
Amalia Macali ◽  
...  
Keyword(s):  
Network Topology ◽  
Disease Gene ◽  
Gene Prediction ◽  
Knowledge Bases ◽  
Biological Knowledge ◽  
Disease Genes ◽  
Human Interactome ◽  
Disease Gene Prediction ◽  
Disease Associations ◽  
Functional Features

Disease gene prediction is to date one of the main computational challenges of precision medicine. It is still uncertain if disease genes have unique functional properties that distinguish them from other non-disease genes or, from a network perspective, if they are located randomly in the interactome or show specific patterns in the network topology. In this study, we propose a new method for disease gene prediction based on the use of biological knowledge-bases (gene-disease associations, genes functional annotations, etc.) and interactome network topology. The proposed algorithm called MOSES is based on the definition of two somewhat opposing sets of genes both disease-specific from different perspectives: warm seeds (i.e., disease genes obtained from databases) and cold seeds (genes far from the disease genes on the interactome and not involved in their biological functions). The application of MOSES to a set of 40 diseases showed that the suggested putative disease genes are significantly enriched in their reference disease. Reassuringly, known and predicted disease genes together, tend to form a connected network module on the human interactome, mitigating the scattered distribution of disease genes which is probably due to both the paucity of disease-gene associations and the incompleteness of the interactome.

scholarly journals Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

2018 ◽  
Author(s):  
Lucilla Pizzo ◽  
Matthew Jensen ◽  
Andrew Polyak ◽  
Jill A. Rosenfeld ◽  
Katrin Mannik ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Background ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Disease Genes ◽  
Complete Evaluation ◽  
Rare Cnvs ◽  
Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

Exome sequencing as a tool for Mendelian disease gene discovery

2011 ◽  
Vol 12 (11) ◽  
pp. 745-755 ◽  
Author(s):  
Michael J. Bamshad ◽  
Sarah B. Ng ◽  
Abigail W. Bigham ◽  
Holly K. Tabor ◽  
Mary J. Emond ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Disease Gene ◽  
Gene Discovery ◽  
Mendelian Disease ◽  
Disease Gene Discovery
Sign in / Sign up

Export Citation Format

Share Document