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The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell prolifera...
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... detected mutations and structural variants are described in accordance with the HGVS (Human Genome Variation Society) nomenclature guidelines, and are reported in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) as 'pathogenic' or 'likely pathogenic' (Table 2). Exon numbering was performed using systematic numbering (as opposed to legacy numbering), numbering the first exon of the respective DYRK1A transcript NM_001396.3 as 1, as recommended. ...
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... 9 of the 10 patients tested (#7's parental samples were unavailable), the mutations occurred de novo (see Table 2). Seven patients were found to harbor heterozygous frameshift or nonsense mutations, localized between exons 5 and 9, of DYRK1A (Table 2 and Figure 2). ...
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... 9 of the 10 patients tested (#7's parental samples were unavailable), the mutations occurred de novo (see Table 2). Seven patients were found to harbor heterozygous frameshift or nonsense mutations, localized between exons 5 and 9, of DYRK1A (Table 2 and Figure 2). Two of our ten cases (patients #4 and #9) had heterozygous, non-synonymous, missense mutations. ...
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... residue is conserved across vertebrates and is predicted to be deleterious by two out of three prediction software programs (Mutation Taster: 0.99 and Polyphen2 HumDiv: 0.9; Sift: 0.21, ie tolerated). Patient #6 from this study has a heterozygous 1.7 Mb interstitial deletion that includes DYRK1A and an additional 11 genes (SIM2, HLCS, RIPPLY3, PIGP, TTC3, DSCR3, KCNJ6, DSCR4, DSCR8, KCNJ15 and 3ʹ end of ERG; see Table 2). Heterozygous deletion of these other 11 genes did not appear to increase the severity of this patient's phenotype. ...
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Citations
... encodes a dual-specificity tyrosine-phosphorylation-regulated kinase, playing a pivotal role in neurodevelopment. This gene's mutations result in variable clinical presentations, contributing to the limited recognition of this rare condition [3]. ...
Autosomal Dominant Mental Retardation Type 7 is a disorder caused by pathogenic variants in the DYRK1A gene. Clinical features associated with this gene mutation include focal dysmorphism, developmental delay, and epilepsy. In this report, we present a case of an 8-year-old boy with a DYRK1A gene mutation, whose clinical manifestations underscore the rarity and clinical challenges of this genetic condition. The patient is a known case of global developmental delay with intractable epilepsy on multiple anti-epileptic medications. Upon examination, the patient showed delayed developmental milestones, hypotonia with brisk deep tendon reflexes, as well as dysmorphic features in the form of microcephaly, deep-set eyes, prominent ears, and a short nose. MRI was done, and findings were suggestive of a DYRK1A gene mutation. The diagnosis was later confirmed by Whole Exome Sequencing (WES). Our report aims to contribute to the growing knowledge about DYRK1A mutations, facilitating a better understanding of the associated clinical features and implications for patient care.
... DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase 1A) is a protein kinase encoded on human chromosome 21 [1][2][3] . The gene is dosage-sensitive with an impact on neurodevelopment 4 . ...
... Several publications refer to a typical gestalt or common dysmorphisms 1,3,13,15,18,20 . All patients in this report had a thin upper lip, and deep-set eyes were described in all but one (Fig. 1). ...
... The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. The severity of the neurodevelopmental disorder is variable in DYRK1A syndrome (Courcet et al., 2012;Bronicki et al., 2015;Ji et al., 2015;van Bon et al., 2016;Evers et al., 2017;Fenster et al., 2022). ...
... Motor, language, and hand-eye coordination; visual performance; and practical reasoning fell below the normal range. These clinical manifestations were consistent with previous reports (Courcet et al., 2012;Bronicki et al., 2015;Ji et al., 2015;van Bon et al., 2016;Evers et al., 2017). Qiao et al. identified a novel mutation c.930C>A of DYRK1A in a 4-year-old Chinese girl, which with typical facial dysmorphisms included deep-set eyes, pointed nasal tip, large ears, a downturned mouth, and micrognathia. ...
Background
Intellectual developmental disorder 7 (also named DYRK1A syndrome) is an autosomal dominant disease. The main clinical features of DYRK1A syndrome include intellectual disability, microcephaly, and developmental delay. This study aimed to identify pathogenic variants in a Chinese girl with developmental delay, impaired social interaction, and autistic behavior.
Case presentation
The case was a 6-year-old girl. Clinical symptoms of the patient mainly included developmental delay, seizures, autistic behavior and impaired social interaction. The patient presented with microcephaly, bushy eyebrows, a short lingual frenum, binocular esotropia, bilateral valgus and external rotation, and walked with an abnormal gait. Using whole-exome sequencing, we identified a 9,424 bp de novo heterozygous deletion (containing coding exons 10, 11, and 12, and partial sequences of non-coding exon 12) in DYRK1A, which is responsible for DYRK1A syndrome. The DYRK1A variant is classified as pathogenic according to the criteria of the American College of Medical Genetics and Genomics.
Conclusions
The findings of this study augment the data regarding the pathogenic variants of DYRK1A and provide important information for molecular diagnosis.
... Trio-WES analysis identified a de novo reported pathogenic heterozygous variant (NM_001396.4:c.763C>T; p.Arg255*; rs724159948) in DYRK1A (Bronicki et al., 2015). ...
DYRK1A-related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable.
... Dental anomalies and cardiac defects are described as well (6,9). Overall, patients affected with DYRK1A mutations experience feeding difficulties, which are responsible for imbalances in weight gain after birth or for short stature (10). Interestingly enough, in the present paper, we report the case of a teenager who was operated upon for a spleen torsion with anomalous gut fixation and who was affected by DYRK1A syndrome. ...
... Infantino et al. 10.3389/fped.2022.936732 ...
DYRK1A syndrome has been extensively studied primarily with regard to neurologic and other phenotypic features such as skeleton and craniofacial alterations. In the present paper, we aim to highlight unusual anomalies associated with a DYRK1A mutation: a 17-year-old female patient with language and cognitive delay, microcephaly, and an autistic disorder, who was operated upon for spleen torsion with anomalous gut fixation.
... In addition to the typical dysmorphic symptoms of MRD7, our patient presented with distinct long slender fingers ( Figure 1D). To date, two reports describe tapered fingers in children with MRD7 [5,19]. The long slender fingers may become more pronounced or noticeable with age. ...
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.
... The phenotypic spectrum of DYRK1A syndrome has become more delineated after subsequent case report descriptions of similar manifestations due to different pathogenic variants in DYRK1A gene. Common clinical features observed in these cases include peculiar dysmorphic facies, speech impairment, intellectual disability with a variable frequency of microcephaly, and epilepsy [1,5,[7][8][9][10]. Based on a previous review study, eighty-four people with DYRK1A variants were reported; 60.7% had loss of function variants, 17.9% had missense variants, 11.9% had splice-site variants, and 8.3% had larger deletions. ...
DYRK1A disorder is among the most frequent monogenic forms of intellectual disability (ID). The majority of cases have been reported to be due to de novo pathogenic variants in DYRK1A gene. This report describes the second case of inherited DYRK1A syndrome that had created issues around variant classification due to its inheritance from an apparently healthy mosaic mother.
... All these mutations cause characteristic features that de ne a well-recognizable syndrome of ID/ASD known as MRD7 (Mental Retardation Dominant 7, OMIM 614104) or DYRK1A-intellectual disability syndrome (DYRK1A syndrome for short, ORPHA 464306). 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]. ...
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.
... feeding difficulties, microcephaly, epilepsy, brain MRI abnormalities, growth retardation and peculiar facial gestalt. [1][2][3][4][5][6][7][8][9] Wiedemann-Steiner syndrome (WSS, MIM#605130) is an autosomal dominant genetic syndrome caused by mutations in the KMT2A (Lysine methyltransferase 2A) gene located on chromosome 11 (11q23.3). ...
... In the DYRK1A syndrome, simple case reports or cohort analysis have highlighted the presence of ASD, attention deficit disorder with or without hyperactivity (ADHD), anxiety disorders and stereotyped behaviors, with variable frequencies. 1,4,[6][7][8][9]17 This is also the case in WSS, where descriptive studies have reported the presence of ASD, ADHD, anxiety disorders and aggressive behavior in individuals. 11,12,14,18 For both syndromes, individual behaviors described in the literature are rarely based on validated questionnaires and standardized tools. ...
DYRK1A and Wiedemann–Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient‐driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.
... For neurogenesis, DYRK1A is involved in brain growth and development by regulating neurogenesis, neural plasticity, and survival. Phosphorylation regulates the polarization and depolarization of actin filaments as well as aggregation of the DYRK1A-actin complexes ( 4 ; Guo et al., 2010;Bronicki et al., 2015). DYRK1A expression increased 1.9-folds, 3.5-folds, and 3.2-folds in new-borns, infants, and adults' frontal cortex with DS on the actin cytoskeleton protein when compared with normal controls. ...
Individuals with Down syndrome (DS) suffer from developmental delay, intellectual disability, and an early-onset of neurodegeneration, Alzheimer’s-like disease, or precocious dementia due to an extra chromosome 21. Studying the changes in anatomical, cellular, and molecular levels involved may help to understand the pathogenesis and develop target treatments, not just medical, but also surgical, cell and gene therapy, etc., for individuals with DS. Here we aim to identify key neurodevelopmental manifestations, locate knowledge gaps, and try to build molecular networks to better understand the mechanisms and clinical importance. We summarize current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans. Understanding the alterations and characteristics of developing Down syndrome will help target treatment to improve the clinical outcomes. Early targeted intervention/therapy for the manifestations associated with DS in either the prenatal or postnatal period may be useful to rescue the neuropathology and neurodegeneration in DS.
