Characterization of phenotypic range in <scp><i>DYRK1A</i></scp> haploinsufficiency syndrome using standardized behavioral measures

Fenster, Rebecca; Ziegler, Alban; Kentros, Catherine; Geltzeiler, Alexa R.; Snyder, LeeAnne Green; Brooks, Elizabeth; Chung, Wendy K.

doi:10.1002/ajmg.a.62721

Cited by 9 publications

(14 citation statements)

References 23 publications

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“…We identified a novel de novo heterozygous variant in the DYRK1A gene, i.e., c.848dup, p.(Asn283Lysfs*6) in our patient and diagnosed him with MRD7. The variants associated with MRD7 are widely distributed in the DYRK1A gene [ 3 ]. Many of these variants introduce a premature stop codon via nonsense, frameshift, and splice site variants, leading to a loss of function [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

“…The variants associated with MRD7 are widely distributed in the DYRK1A gene [ 3 ]. Many of these variants introduce a premature stop codon via nonsense, frameshift, and splice site variants, leading to a loss of function [ 3 ]. Contrarily, several missense variants associated with MRD7 have been reported, primarily located in the kinase domain encoded by the DYRK1A gene, and affecting its catalytic function [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Intellectual developmental disorder, autosomal dominant 7 (MRD7; OMIM 614104), also known as DYRK1A (haploinsufficiency) syndrome, is a rare autosomal dominant disease with a prevalence of less than 1/1,000,000 [1][2][3]. MRD7 is characterized by microcephaly, intellectual disability, speech delay, feeding difficulties, and distinct facial dysmorphisms, including prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia [1,4,5].…”

Section: Introductionmentioning

confidence: 99%

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Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7

Obara

Abe

Toyoshima

2023

Cureus

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Intellectual developmental disorder, autosomal dominant 7 (MRD7; OMIM 614104) is a rare disease characterized by microcephaly, intellectual disability, speech delay, feeding difficulties, and facial dysmorphisms. This disorder is caused by pathogenic/likely pathogenic variants of the DYRK1A gene, which encodes dual-specificity tyrosine-phosphorylation-regulated kinase 1A. Here, we report a case of MRD7 that was diagnosed using Face2Gene and whole-exome sequencing (WES). A 22-year-old man presented with microcephaly, intellectual disability, slender body, long slender fingers, and facial dysmorphisms. He was previously diagnosed with Cornelia de Lange syndrome (CdLS) at four years of age. However, his CdLS clinical diagnostic score was low at 22 years of age. The Face2Gene application introduced several candidate diseases including MRD7. Finally, by utilizing WES and Sanger sequencing analysis of cloned cDNA, we identified a novel heterozygous duplication variant (c.848dup, p.(Asn283LysfsTer6)) in the DYRK1A gene, which introduces a premature stop codon. This report provides more information about the phenotypic spectrum of a young adult patient with MRD7. Face2Gene helped us introduce candidate diseases of the patient. Registering further genetically confirmed cases with MRD7 will improve the accuracy of the diagnostic recommendations in Face2Gene. Moreover, WES is a powerful tool for diagnosing rare genetic diseases, such as MRD7.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7

Obara

Abe

Toyoshima

2023

Cureus

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“…Core symptoms of DYRK1A syndrome include general DD, microcephaly, moderate to severe ID, speech delay or an absence of communicative language, motor di culties and a distinctive facial gestalt [14,[21][22][23]. Core symptoms in affected patients are often accompanied by ASD or autistic features and epilepsy [14,23,24]. Although the impact of DYRK1A mutations on brain morphology has not been studied systematically, the most frequent magnetic resonance image (MRI) changes reported in affected cases are cortical atrophy, enlarged ventricles, a small brainstem, delayed myelination and hypoplasia of the corpus callosum (CC) [25].…”

Section: Introductionmentioning

confidence: 99%

DYRK1A haploinsufficiency affects the development of astroglia and oligodendroglia, and axonal conductivity in the brain

Pijuan

Balducci

Soto-Sánchez

et al. 2022

Preprint

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Background: The correct development and activity of neurons and glial cells, and the interplay between them, is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase that influences neurogenesis and the morphological differentiation of neurons. Indeed, it is a gene associated with a risk of autism spectrum disorders. DYRK1A loss-of-function mutations cause a rare disorder in heterozygosity characterized by developmental delay, microcephaly, moderate-to-severe intellectual disability, speech delay or the absence of communicative language, motor dysfunctions and a distinctive facial gestalt. Ritualized behaviours and/or autism are also frequent traits in this disorder. As such, glial cell development and myelination in the brain have been explored in relation to DYRK1A haploinsufficiency syndrome.Methods: Using cell-specific markers, the developmental trajectories of cortical macroglial cells were analysed in brain sections of Dyrk1a+/- mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome. In combination with in utero electroporation, the ultrastructure of the brain white matter was studied by electron microscopy and the characteristics of the nodes of Ranvier by immunofluorescence. Myelin protein was assessed by immunoblotting and electrophysiology was performed to measure conduction velocities of evoked compound action potentials in the corpus callosum.Results: In Dyrk1a+/- mice the development of glial cells that populate the prospective neocortex was altered. An increase in astrogliogenesis produced an excess of astrocytes that persisted into adulthood, in conjunction with a delay in the production of oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a+/- mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a+/- mutants. All these abnormalities are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions.Conclusions: The results obtained here indicate that disrupted macroglial development and white matter myelination contribute to the core neurological symptoms of DYRK1A syndrome, paving the way to design pharmacological interventions that ameliorate or revert these symptoms postnatally.

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“…Core symptoms of DYRK1A syndrome include general developmental delay, microcephaly, moderate to severe ID, speech delay or an absence of communicative language, motor difficulties and a distinctive facial gestalt 10 , 16 , 17 . Core symptoms in affected patients are often accompanied by ASD or autistic features and epilepsy 10 , 17 , 18 . Although the impact of DYRK1A mutations on brain morphology has not been studied systematically, the most frequent magnetic resonance image changes reported in affected cases are cortical atrophy, enlarged ventricles, a small brainstem, delayed myelination and hypoplasia of the corpus callosum (CC) 19 .…”

Section: Introductionmentioning

confidence: 99%

Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome

Pijuan

Balducci

Soto-Sánchez

et al. 2022

Sci Rep

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The correct development and activity of neurons and glial cells is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase involved in the neuropathology associated with Down syndrome that influences neurogenesis and the morphological differentiation of neurons. DYRK1A loss-of-function mutations in heterozygosity cause a well-recognizable syndrome of intellectual disability and autism spectrum disorder. In this study, we analysed the developmental trajectories of macroglial cells and the properties of the corpus callosum, the major white matter tract of the brain, in Dyrk1a+/− mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome. We found that Dyrk1a+/− haploinsufficient mutants present an increase in astrogliogenesis in the neocortex and a delay in the production of cortical oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a+/− mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a+/− mutants. All these alterations are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions. These alterations highlight the relevance of glial cell abnormalities in neurodevelopmental disorders.

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Characterization of phenotypic range in DYRK1A haploinsufficiency syndrome using standardized behavioral measures

Cited by 9 publications

References 23 publications

Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7

Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7

DYRK1A haploinsufficiency affects the development of astroglia and oligodendroglia, and axonal conductivity in the brain

Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome

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