Corrigendum: Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth

Loveday, Chey; Tatton‐Brown, Katrina; Clarke, Matthew; Westwood, Isaac M.; Renwick, Anthony; Ramsay, Emma; Németh, Andrea H.; Campbell, Jennifer; Joss, Shelagh; Gardner, McKinlay; Zachariou, Anna; Elliott, Anna; Ruark, Elise; Montfort, Rob van; Rahman, Nazneen

doi:10.1093/hmg/ddy424

Cited by 25 publications

(41 citation statements)

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“…29 Some role in overgrowth was either known, or has been proposed, for the remainder of these, apart from HIST1H1E (see GeneReviews by Eng in Web Resources). 6,9,10,12,[29][30][31][32][33][34][35] HIST1H1E Mutations Cause OGID We present here data showing that certain HIST1H1E mutations cause OGID. Through exome sequencing we identified five unrelated probands-COG0405, COG0412, COG0552, COG1739, and COG1832-with heterozygous HIST1H1E protein truncating variants (PTVs) (Figure 2, Tables 1 and S1).…”

Section: Contribution Of Gene Mutations To Ogidmentioning

confidence: 60%

“…3,4 The advent of next-generation sequencing has been the foremost reason for this progress and has allowed elucidation of the genetic causes of clinically established syndromes and the delineation of new syndromes. [5][6][7][8][9][10][11][12] Despite these advances, many individuals with OGID remain without a genetic diagnosis. In addition, the relative contribution of the different genes to OGID is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

Tatton‐Brown

Loveday

Yost

et al. 2017

The American Journal of Human Genetics

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172

218

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To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.

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Section: Contribution Of Gene Mutations To Ogidmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

Tatton‐Brown

Loveday

Yost

et al. 2017

The American Journal of Human Genetics

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172

218

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“…Reanalysis of WES data at 12 months in undiagnosed individuals identified new diagnoses in four families, increasing the overall diagnostic rate from 30 to 41%. Two diagnoses were due to interim publications of new disease-gene associations including PPP2R5D linked to ID and overgrowth 21 and TANGO2 linked to episodic metabolic crises and neurodegeneration 22,23 (patients 8-10, Table 1). One additional large family with autosomal dominant retinitis pigmentosa had a new finding of a splice-site variant in a retinitis pigmentosa-related gene, PRPF31 (c.527+3A > G; patient 19).…”

Section: Reanalysis At a 12-month Time Point Boosts Diagnosesmentioning

confidence: 99%

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Ewans

Schofield

Shrestha

et al. 2018

Genetics in Medicine

155

149

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PurposeWhole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.MethodsWES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).ResultsReanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.ConclusionEarly application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.GENETICS in MEDICINE advance online publication, 29 March 2018; doi:10.1038/gim.2018.39.

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“…By far the largest number of reported PP2A mutated cases harbor de novo pathogenic variants in PPP2R5D, encoding the regulatory B56δ subunit (25 patients). 4,5,12,13 All but one (p.P53S) of the B56δ variants that were biochemically characterized (p.E198K, p.E200K, p.P210R, and p.W207R) showed decreased A and C binding, suggesting a dominantnegative mode of action. 4 PPP2R5C (encoding B56γ; one case) and PPP2R5B (encoding B56β; one case) are two additional PP2A genes, pathogenic variants of which were associated with ID and overgrowth.…”

Section: Introductionmentioning

confidence: 99%

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Lenaerts

Reynhout

Verbinnen

et al. 2021

Genetics in Medicine

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Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

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Corrigendum: Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth

Cited by 25 publications

References 0 publications

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

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