Pathogenic<i>ASXL1</i>somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

Carlston, Colleen M.; O’Donnell-Luria, Anne H.; Underhill, Hunter R.; Cummings, Beryl B.; Weisburd, Ben; Minikel, Eric Vallabh; Birnbaum, Daniel; Tvrdik, Tatiana; MacArthur, Daniel G.; Mao, Rong

doi:10.1101/090720

Cited by 21 publications

(31 citation statements)

References 34 publications

(52 reference statements)

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“…Interestingly, DNMT3A p.(Arg882His) and p.(Arg882Cys) variants are listed in 66 and 43 purportedly healthy individuals in the Exome Aggregation Consortium (ExAC) database, respectively. However, the median variant allele fraction in these individuals was 19%, suggesting that the ExAC database is confounded by somatic variants in genes frequently mutated in patients with age‐related clonal hematopoiesis (Carlston et al, ). The appearance of DNMT3A p.(Arg882His) and p.(Arg882Cys) in ExAC is likely attributable to somatic mosaicism.…”

Section: Discussionmentioning

confidence: 99%

The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Shen

Heeley

Carlston

et al. 2017

American J of Med Genetics Pt A

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De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.

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Section: Discussionmentioning

confidence: 99%

The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Shen

Heeley

Carlston

et al. 2017

American J of Med Genetics Pt A

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“…In addition, databases of large sequencing efforts are consulted to search for SNVs that are believed to be phenotypically neutral since they were detected in healthy individuals. This strategy should be used with caution since some of the databases contain SNVs that occur as somatic mosaics [Carlston et al, 2017]. By WES and WGS of large cohorts of patients with specific forms of craniosynostosis, be it as an isolated phenotype or as part of a syndrome, a considerable number of novel candidate genes and mutations have been uncovered [Roscioli et al, 2013;Miller et al, 2017;Timberlake et al, 2017;Timberlake and Persing, 2018].…”

Section: Craniosynostosis Gene Identificationmentioning

confidence: 99%

Structural Genome Variations Related to Craniosynostosis

Poot¹

2018

Mol Syndromol

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Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.

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“…The above examples illustrate only a few of the types of positional patterns and error modes that may appear upon manual curation. Additional examples have been reported previously 95,96 , and a companion paper further illustrates the importance of transcript expression-aware annotation 24 . For anyone considering developing a drug against a target, the types of analyses described above are only a first step.…”

Section: Figure 5 Non-random Positional Distributions Of Plof Varianmentioning

confidence: 61%

Evaluating potential drug targets through human loss-of-function genetic variation

Minikel¹,

Karczewski²,

Martin³

et al. 2019

Preprint

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Human genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerful in vivo models of human genetic "knockouts" to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of individual humans harboring "knockouts" (biallelic gene inactivation), followed by individual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous individuals in outbred populations. Sampling of diverse bottlenecked populations and consanguineous individuals will aid in identification of total "knockouts". Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF individuals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations. 84.

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PathogenicASXL1somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

Cited by 21 publications

References 34 publications

The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Structural Genome Variations Related to Craniosynostosis

Evaluating potential drug targets through human loss-of-function genetic variation

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