Mendelian Gene Discovery: Fast and Furious with No End in Sight

Bamshad, Michael J.; Nickerson, Deborah A.; Chong, Jessica X.

doi:10.1016/j.ajhg.2019.07.011

Cited by 202 publications

(205 citation statements)

References 38 publications

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“…Potential reasons for the modest molecular diagnostic rate are manifold. At present, we are aware of only 6000 human disease genes, and we suspect that there are many more with estimates of 6000-13,000 disease genes yet to be identified [16]. Furthermore, the variation responsible for the transient lactic acidosis may not be detectable by "exon" level methods such as variation in the non-coding region, a chromosomal deletion or duplication, complex chromosomal rearrangement(s) or expansion mutations.…”

Section: Resultsmentioning

confidence: 99%

Autosomal dominant transmission of transient neonatal lactic acidosis: a case report

2020

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Background: Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance. Case presentation: Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-topyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation. Conclusion: We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents.

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Section: Resultsmentioning

confidence: 99%

Autosomal dominant transmission of transient neonatal lactic acidosis: a case report

2020

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“…In the past, human geneticists mostly relied on large family pedigrees to identify genes associated with disease (Wijsman, 2012). However, with the advent of next-generation sequencing technology, it is now often possible to identify one or a few variants that are associated with disease in a single individual (Bamshad et al, 2019;Posey et al, 2019). Typically, 40-50% of pediatric diseases can be diagnosed by identifying variants in previously described disease genes using whole-exome sequencing (WES) combined with assessment of copy number variations (CNVs) (Liu et al, 2019;Ngo et al, 2020), or by performing whole-genome sequencing (WGS).…”

Section: Advances In Human Genetics Technologies and Rare Disease DImentioning

confidence: 99%

“…Despite these efforts, there are still millions of individuals with undiagnosed diseases, and it is estimated that 6000-13,000 human genes remain to be associated with diseases (Bamshad et al, 2019). The National Institutes of Health has established and supported consortia such as the Centers for Mendelian Genomics (CMG) to uncover the genetics of Mendelian disease (Bamshad et al, 2012;Posey et al, 2019) and the Undiagnosed Diseases Network (UDN) (Ramoni et al, 2017;Splinter et al, 2018) to diagnose patients with rare diseases who typically undergo a long diagnostic odyssey.…”

Section: Advances In Human Genetics Technologies and Rare Disease DImentioning

confidence: 99%

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Link

Bellen

2020

Development

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Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila, can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways.

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“…However, the detection of a GWAS signal alone does not identify the causal gene at a locus and so substantial bioinformatics and experimental effort is still required to convert this new genetic knowledge into useful biological insight. At the other end of the spectrum, Mendelian monogenic disease research has benefitted tremendously from recent sequencing methods, which helped to detect and define the causal genes in >1,000 Mendelian conditions (Bamshad, Nickerson, & Chong, 2019). In contrast to complex trait loci, high penetrance, big effect size and typically coding effect of Mendelian perturbations mean the causal gene is more easily detected using statistical methods alone, resulting in a direct link between phenotype and gene.…”

Section: Introductionmentioning

confidence: 99%

“…There is a large scope for an increase in numbers for genes associated with Mendelian disease. Estimates (depending on the type of constraints on the gene) are at between 5,000 to 10,000 potential novel Mendelian disease genes (Bamshad et al, 2019) and proportionately higher number of Mendelian diseases due to pleiotropy (Chong et al, 2015). MendelVar will be regularly updated with new findings on Mendelian disease genes.…”

Section: Introductionmentioning

confidence: 99%

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

Sobczyk

Gaunt

Paternoster

2020

Preprint

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Gene prioritisation at GWAS loci necessities careful assembly and examination of different types of molecular evidence to arrive at a set of plausible candidates. In many human traits, common small-effect mutations may subtly dysregulate the function of the very same genes which are impacted by rare, large-effect mutations causing Mendelian disease of similar phenotype. However, information on gene-Mendelian disease associations, rare pathogenic mutations driving the disease, and the disease phenotype ontology is dispersed across many data sources and does not integrate easily with enrichment analysis.MendelVar is a new webserver facilitating transfer of knowledge from Mendelian disease research into interpretation of genetic associations from GWAS of complex traits.MendelVar allows querying of pre-defined or LD-determined genomic intervals against a comprehensive integrated database to find overlap with genes linked to Mendelian disease. Next, MendelVar looks for enrichment of any Human Phenotype Ontology, DiseaseOntology and other ontology/pathway terms associated with identified Mendelian genes. In addition, MendelVar provides a list of all overlapping pathogenic and likely pathogenic variants for Mendelian disease sourced from ClinVar. Inclusion of information obtained from MendelVar in post-GWAS gene annotation pipelinescan strengthen the case for causal importance of some genes. Moreover, as genes with Mendelian disease evidence may make for more successful drug targets, this may be particularly useful in drug discovery pipelines. Taking GWAS summary statistics for malepattern baldness, intelligence and atopic dermatitis, we demonstrate the use of MendelVar in prioritizing candidate genes at these loci which are linked to relevant enriched ontology terms. MendelVar is freely available at https

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Mendelian Gene Discovery: Fast and Furious with No End in Sight

Cited by 202 publications

References 38 publications

Autosomal dominant transmission of transient neonatal lactic acidosis: a case report

Autosomal dominant transmission of transient neonatal lactic acidosis: a case report

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

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