The<i>DYRK1A</i>gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy

Courcet, Jean-Benoît; Faivre, Laurence; Malzac, Perrine; Masurel‐Paulet, Alice; Lopez, Estelle; Callier, Patrick; Lambert, Laëtitia; Lemesle, M.; Thévenon, Julien; Gigot, Nadège; Duplomb, Laurence; Ragon, Clémence; Marle, Nathalie; Mosca-Boidron, Anne-Laure; Huet, Frédéric; Philippe, Christophe; Moncla, Anne; Thauvin‐Robinet, Christel

doi:10.1136/jmedgenet-2012-101251

Cited by 119 publications

(113 citation statements)

References 32 publications

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“…There were some strikingly similar features between members of our cohort and the features of previously reported individuals with a similar genotype, [10][11][12][13][14][15][16][17] indicating that this is a recognizable syndrome. Microcephaly, IUGR, brain abnormalities consistent with cerebral hypomyelination, global DD, ID, severe speech delay, seizures, broadbased gait, short stature, minor skeletal anomalies, and distinct facial gestalt were the most commonly shared features.…”

Section: Resultssupporting

confidence: 84%

“…[10][11][12][13][14][15][16] These are included in Supplementary Table S1. Specific evidence supporting the role of DYRK1A individuals includes the deletion of the non-coding 5′-UTR (NM_130436.3) in one published case, 11 as well as the disruption of DYRK1A by translocation in two cases reported by Moller et al 10 Furthermore, in the Database of Genomic Variants, there are only two self-reported phenotypically normal individuals with exonic losses of DYRK1A (8 Kb and 181 Kb). There are no segmental duplications flanking the deletion breakpoints.…”

Section: Resultsmentioning

confidence: 99%

“…A clinical geneticist provided phenotypic information for all patients. The clinical features of our cohort (n = 14, Table 1) are summarized and were assessed for both overlap and divergence among the cohort and compared with the 13 individuals in published reports, [10][11][12][13][14][15][16][17] as shown in Supplementary Table S1.…”

Section: Phenotypic Analysismentioning

confidence: 99%

“…5,6 Furthermore, data from both animal models and humans have suggested that decreased DYRK1A expression is also pathogenic. [7][8][9] Pathogenic variants in DYRK1A resulting in haploinsufficiency of the gene have recently been proposed to cause intellectual disability (ID), mental retardation autosomal dominant type 7 (MIM 614104) in individuals with translocations, 10 single-nucleotide variants (SNVs), 11,12 and intragenic microdeletions 11,[13][14][15][16][17] disrupting only DYRK1A.…”

Section: Introductionmentioning

confidence: 99%

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DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Phenotypic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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“…Previous reports indicated that 21q22 micro deletions including only DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) gene was found in patients presented with microcephaly, growth retardation, epilepsy, delayed speech and similar features such as low set ears, long philtrum, micrognathia [4,14,23]. Deletion including the 5` region of the DYRK1A gene was observed in another patient with microcephaly, seizures and dysmorphic features [24]. It was suggested that the DYRK1A gene might be the causative gene responsible for most of the clinical features observed in interstitial deletion of chromosome 21.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

Hussein¹

2015

J Mol Biomark Diagn

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We report on a new case with developmental delay, dysmorphic features, holoprosencephaly that showed deletion in long arm of chromosome 21 (21q22.13-q22.3). The patient is a male 3 months old presented with frontonasal dysplasia, scoliosis, abnormal ears, VSD, hypospadias, undescended testis. MRI has shown holoprosencephaly and agenesis of corpus callosum. Array-comparative genomic hybridization using the Agilent 2×400 oligoarray showed an interstitial deletion in chr21q22.13-q22.3, (start-end: 36,854,967-46,006,008 bp) deletion size is 9 Mb (9,151,042 bp) and includes 75 genes (Data base of genomic variants, hg18). The deletion was found to be maternal in origin. The findings from this report underscore the role of the genes at chromosome 21q22.13-q22.3 in brain development and indicate the usefulness of array-CGH in identification of the deletion size and detection of genes that could be correlated to the patient's phenotype.

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Autism Spectrum Disorders

Anderson

2018

Developmental Neuropathology

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TheDYRK1Agene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy

Cited by 119 publications

References 32 publications

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

Autism Spectrum Disorders

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