Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation

Carion, Nathalie; Briand, Audrey; Cuisset, Laurence; Pacot, Laurence; Afenjar, Alexandra; Bienvenu, Thierry

doi:10.1016/j.gene.2020.144793

Cited by 4 publications

(1 citation statement)

References 17 publications

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“…Variants in DYRK1A were identified during genetic analyses carried out in individuals referred to clinical genetic services for intellectual disability in France, Denmark and Switzerland: CGH-array, direct Sanger sequencing of DYRK1A coding sequences, targeted next generation sequencing of genes involved in ID (TES)(Redin et al , 2014; Carion et al , 2020; Nasser et al , 2020), trio or simplex clinical or exome sequencing (CES, ES). The variants reported here were confirmed by an additional method.…”

Section: Methodsmentioning

confidence: 99%

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Courraud

Chater‐Diehl

Durand

et al. 2021

Preprint

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ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboring DYRK1A variants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurring de novo.

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Section: Methodsmentioning

confidence: 99%

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Courraud

Chater‐Diehl

Durand

et al. 2021

Preprint

Self Cite

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Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet

Melikishvili¹,

Bienvenu²,

Tabatadze³

et al. 2022

Seizure

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Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Courraud

Chater‐Diehl

Durand

et al. 2021

Genetics in Medicine

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PURPOSE: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. METHODS: We reported clinical and molecular data for fifty individuals with ID harboring DYRK1A variants and developed i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. RESULTS: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. CONCLUSION: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene. ACCEPTED MANUSCRIPT -CLEAN COPYand analyzed as previously described 20 , a total of n=774,590 probes were analyzed for differential methylation. Standard quality control metrics showed good data quality for all samples except Ind#20. Briefly, limma regression with covariates age, sex, and five predicted blood cell types identified a DNAm signature with a Benjamini-Hochberg adjusted p-value<0.05 and 10% methylation difference. Next, we developed a support vector machine (SVM) model with linear kernel trained on including non-redundant CpG sites 20 using the methylation values for the discovery cases vs. controls. The model generated scores ranging between 0 and 1 for tested samples, classifying samples as "positive" (score>0.5) or "negative" (score<0.5). Additional neurotypical controls (n=94) and DYRK1A LoF validation samples (n=6) were scored to test model specificity and sensitivity respectively, and samples with pathogenic KMT2A (n=8) and ARID1B (n=4) variants and DYRK1A missense and distal frameshift (n=11) variants were tested. RESULTS Identification of genetic variants in DYRK1A in individuals with IDWe collected molecular and clinical information from 50 individuals with ID (44 never reported and six previously reported 6,7 ) carrying a variant in DYRK1A identified in clinical and diagnostic laboratories: structural variants deleting or interrupting DYRK1A and recurrent or novel nonsense, frameshift, splice and missense variants (Table 1, Figure S1). When blood or fibroblast samples were available, we characterized the consequences of these variants on DYRK1A mRNA by RNA-sequencing and RT-qPCR (Figure S2, Supplementary Text). For one variant, c.1978del, occurring in the last exon of the gene (Ind #18), the mutant transcripts escape to nonsense mRNA mediated decay (NMD) and result in a truncated protein p.Se...

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Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation

Cited by 4 publications

References 17 publications

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

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