Autosomal dominant overhydrated stomatocytosis associated with the heterozygous Rh<scp>AG</scp> mutation F65S: a case of missed heterozygosity due to allelic dropout

Shmukler, Boris E.; Mukodzi, Sally; Andrés, Oliver; Eber, Stefan; Alper, Seth L.

doi:10.1111/bjh.12261

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…There are increasing numbers of studies that discuss the importance of ADO in DNA diagnostic procedures (Tester et al, 2006;Coulet et al, 2010;Medlock et al, 2012;Rossetti et al, 2012;Lam and Mak, 2013;Shmukler et al, 2013;Rhees et al, 2014;Blais et al, 2015;Proost, 2016). This phenomenon was detected in oncogenetics (BRCA1/2 testing), inborn metabolic disease genotyping (FAH testing), hematology research etc (Lam and Mak, 2013;Shmukler et al, 2013;Jeong et al, 2019). We surmise that the actual number of ADO events remains unknown and may significantly exceed the events actually detected.…”

Section: Discussionmentioning

confidence: 99%

Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels

et al. 2021

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Primary cardiomyopathies (CMPs) are monogenic but multi-allelic disorders with dozens of genes involved in pathogenesis. The implementation of next-generation sequencing (NGS) approaches has resulted in more time- and cost-efficient DNA diagnostics of cardiomyopathies. However, the diagnostic yield of genetic testing for each subtype of CMP fails to exceed 60%. The aim of this study was to demonstrate that allelic dropout (ADO) is a common phenomenon that reduces the diagnostic yield in primary cardiomyopathy genetic testing based on targeted gene panels assayed on the Ion Torrent platform. We performed mutational screening with three custom targeted gene panels based on sets of oligoprimers designed automatically using AmpliSeq Designer® containing 1049 primer pairs for 37 genes with a total length of 153 kb. DNA samples from 232 patients were screened with at least one of these targeted gene panels. We detected six ADO events in both IonTorrent PGM (three cases) and capillary Sanger sequencing (three cases) data, identifying ADO-causing variants in all cases. All ADO events occurred due to common or rare single nucleotide variants (SNVs) in the oligoprimer binding sites and were detected because of the presence of “marker” SNVs in the target DNA fragment. We ultimately identified that PCR-based NGS involves a risk of ADO that necessitates the use of Sanger sequencing to validate NGS results. We assume that oligoprimer design without ADO data affects the amplification efficiency of up to 0.77% of amplicons.

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Section: Discussionmentioning

confidence: 99%

Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels

et al. 2021

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“…The causative gene of OHS is RHAG (6p12.3), which encodes an ammonium/carbon dioxide channel (Bruce et al , ). Functional studies have demonstrated that pathogenic variants induce an alteration of the kinetics of the channel, thereby causing an increase of the monovalent cation leak and of intracellular water content (Bruce, ; Stewart et al , ; Genetet et al , ; Shmukler et al , ).…”

Section: Red Blood Cell Membrane Disorders: Classification and Pathogmentioning

confidence: 99%

Advances in understanding the pathogenesis of red cell membrane disorders

2019

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Summary Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main consequences of these genetic alterations are decreased cell deformability and shortened erythrocyte survival. Red blood cell membrane defects encompass a heterogeneous group of haemolytic anaemias caused by either (i) altered membrane structural organisation (hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis and Southeast Asian ovalocytosis) or (ii) altered membrane transport function (overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis or xerocytosis, familial pseudohyperkalaemia and cryohydrocytosis). Herein we provide a comprehensive review of the recent literature on the molecular genetics of erythrocyte membrane defects and their reported clinical consequences. We also describe the effect of low‐expression genetic variants on the high inter‐ and intra‐familial phenotype variability of erythrocyte structural defects.

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“…HSt includes a group of hemolytic anemias characterized by increased cation permeability of RBC membrane, resulting in deregulated cellular volume. A particular form, characterized by increased cellular hydration, is known as hydrocytosis or overhydrated stomatocytosis (OHSt), mainly caused by mutations in the RHAG gene,6 even if milder forms have been associated with mutations in SLC4A1 gene 4.…”

mentioning

confidence: 99%

Overhydrated hereditary stomatocytosis: A rare cause of familiar persistent macrocytosis due to SLC4A1 variants

Marcello

Visconti

Vercellati

et al. 2023

Pediatric Blood & Cancer

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Autosomal dominant overhydrated stomatocytosis associated with the heterozygous RhAG mutation F65S: a case of missed heterozygosity due to allelic dropout

Cited by 4 publications

References 10 publications

Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels

Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels

Advances in understanding the pathogenesis of red cell membrane disorders

Overhydrated hereditary stomatocytosis: A rare cause of familiar persistent macrocytosis due to SLC4A1 variants

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