Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Edvardson, Simon; Nicolae, Claudia M.; Agrawal, Pankaj B.; Mignot, Cyril; Payne, Katelyn; Prasad, Asuri N.; Prasad, Chitra; Sadler, Laurie S.; Nava, Caroline; Mullen, Thomas E.; Begtrup, Amber; Baskin, Berivan; Powis, Zöe; Shaag, Avraham; Keren, Boris; Moldovan, George‐Lucian; Elpeleg, Orly

doi:10.1016/j.ajhg.2017.07.002

Cited by 45 publications

(89 citation statements)

References 28 publications

(31 reference statements)

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“…[8][9][10] More recently, new associations of genes with severe developmental phenotypes and neurodegeneration have been discovered. 11,12 This has been largely possible as a result of high-throughput sequencing methods such as next-generation sequencing (NGS), in conjunction with sequencing databases for control cohorts such as ExAC and gnomAD, [13][14][15][16][17][18][19][20][21] variant prediction, 22 model organism information (e.g., MARRVEL) 23 and crowdsourcing programs, such as GeneMatcher, 24 used for identifying additional cases. These tools have greatly promoted gene discovery and assisted in ascertaining the role of the candidate variants for disease.…”

Section: Introductionmentioning

confidence: 99%

IRF2BPL Is Associated with Neurological Phenotypes

Marcogliese¹,

Shashi²,

Spillmann³

et al. 2018

The American Journal of Human Genetics

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Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

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Section: Introductionmentioning

confidence: 99%

IRF2BPL Is Associated with Neurological Phenotypes

Marcogliese¹,

Shashi²,

Spillmann³

et al. 2018

The American Journal of Human Genetics

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“…The original analysis failed to yield any variant that might be plausibly linked to an intellectual disability or epilepsy phenotype [7]. The data were reanalyzed six months later using an updated panel that (at that point) contained the gene UBTF, that had just been published in connection with an intellectual disability phenotype by Edvardson et al [1]. This allowed for the detection of a heterozygous c.628G>A UBTF variant, which was confirmed by Sanger sequencing and found to be de novo.…”

Section: Case Presentationmentioning

confidence: 99%

“…Recently three independent teams [1][2][3] reported on a new monogenic neurodegenerative disease of childhood associated with a specific monoallelic de novo c.628G>A (p.Glu210Lys) UBTF variant. Together, 12 male and female patients aged 6 to 33 years old were described with a consistent phenotype of normal or close to normal early developmental milestones followed by motor and cognitive regression [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…UBTF (Upstream Binding Transcription Factor, OMIM *600673) gene codes for Upstream Binding Factor (UBF), a protein that acts as a transcription factor for RNA polymerase I, essential for the generation of ribosomal RNA transcripts (rRNA) from ribosomal DNA (rDNA) in the nucleolus [1,2]. The c.628G>A variant confers a gain of function to the protein resulting in increased expression of rDNA and rRNA, which in turn is thought to lead to scavenging of RNA binding proteins, altered RNA disposal machinery and ribosome biogenesis [1], as well as defective DNA damage repair and chromatid cohesion [1,2,4,5].…”

Section: Introductionmentioning

confidence: 99%

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Childhood neurodegeneration associated with a specific UBTF variant: a new case report and review of the literature

et al. 2020

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Background: A new monogenic neurodegenerative disease affecting ribosomal metabolism has recently been identified in association with a monoallelic UBTF putative gain of function variant (NM_001076683.1:c.628G>A, hg19). Phenotype is consistent among these probands with progressive motor, cognitive, and behavioural regression in early to middle childhood. Case presentation: We report on a child with this monoallelic UBTF variant who presented with progressive disease including regression, episodes of subacute deterioration during febrile illnesses and a remarkable EEG pattern with a transient pattern of semi-periodic slow waves. Conclusions: This case further supports the phenotype-genotype correlation of neurodegeneration associated with UBTF c.628G>A. Moreover, it brings new insights into the clinical features and EEG that could possibly serve as diagnostic markers of this otherwise nonspecific phenotype.

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“…8–10 More recently, new genes associated with severe developmental phenotypes and neurodegeneration have been discovered. 11,12 This has been largely possible due to the use of high-throughput sequencing methods such as next-generation sequencing (NGS), in conjunction with sequencing databases for control cohorts such as ExAC and gnomAD 13–21 , variant prediction 22 , model organism information (e.g. MARRVEL.org) 23 and crowdsourcing programs to identify additional cases, such as GeneMatcher.org.…”

Section: Introductionmentioning

confidence: 99%