Alternative titles; symbols
HGNC Approved Gene Symbol: DYRK1A
SNOMEDCT: 1179301003;
Cytogenetic location: 21q22.13 Genomic coordinates (GRCh38) : 21:37,365,573-37,526,358 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.13 | Intellectual developmental disorder, autosomal dominant 7 | 614104 | Autosomal dominant | 3 |
The DYRK1A gene encodes a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family and participates in various cellular processes. It is a highly conserved gene located in the so-called Down Syndrome critical region (DSCR), a part of chromosome 21 that is responsible for the majority of phenotypic features in Down syndrome (190685) (summary by van Bon et al., 2011).
In the course of cloning transcripts from the region of human chromosome 21 that is homologous to the region of mouse chromosome 16 containing the 'weaver' (wv) locus (see 600877), Patil et al. (1995) identified a gene that encodes a serine/threonine-specific protein kinase. The closest relative of this kinase was found to be the Drosophila 'minibrain' gene (mnb) (Tejedor et al., 1995).
Shindoh et al. (1996) performed exon trapping to find exons within YAC clones spanning the 2-Mb Down syndrome critical region of human chromosome 21. Of more than 160 exons isolated, they found 6 that had significant identity at the amino acid level to the Drosophila 'minibrain' gene. Using 1 of these exons as a probe, they cloned the full-length human cDNA from a human fetal brain cDNA library. Sequence analysis of this cDNA revealed an open reading frame encoding a polypeptide of 754 amino acids. Shindoh et al. (1996) stated that this gene, termed MNB by them, represents the human homolog of the Drosophila mnb gene and of the rat Dyrk gene. The rat Dyrk gene differs from it by only 4 amino acids. Northern blot analysis of MNB revealed 2 transcripts of 6.0 and 7.5 kb. The 6.0-kb transcript was found to be present in all tissues examined, with highest levels of expression in skeletal muscle, testis, fetal lung, and fetal kidney. The 7.5-kb transcript was found to be expressed at a relatively lower level and was found only in adult heart, placenta, spleen, and testis. Shindoh et al. (1996) concluded that the human MNB protein may play a significant role in a signaling pathway regulating cell proliferation and may be involved in normal brain development and in the pathogenesis of Down syndrome.
Song et al. (1996) cloned the DYRK gene and its murine counterpart (Dyrk) and compared it to the rat Dyrk gene. The 3 mammalian genes are highly conserved, being more than 99% identical at the protein level over their 763-amino acid open reading frame; in addition, the mammalian genes are 83% identical over 414 amino acids to the smaller 542-amino acid mnb protein of Drosophila. The predicted human and murine proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (days 13, 15, and 17 postcoitus) indicated a differential spatial and temporal pattern of expression, with the most abundant signal localized in brain matter, spinal cord, and retina. The observed expression pattern was coincident with many of the clinical findings in trisomy 21.
Song et al. (1997) found that mouse Dyrk is expressed in frontal brain nuclei during mouse embryogenesis and that it interacts with other proteins. The chromosomal locus of DYRK, its homology to the mnb gene, and the in situ hybridization expression patterns of murine Dyrk, combined with the fact that transgenic mice for a YAC to which Dyrk maps are mentally deficient, suggested to Song et al. (1996) that DYRK may be involved in the abnormal neurogenesis found in Down syndrome. They considered DYRK a good candidate to mediate some of the pleiotropic effects of Down syndrome.
Chen and Antonarakis (1997) used exon trapping to identify human chromosome 21-encoded genes and identified in this way the homolog of the Drosophila mnb gene. By Northern analysis they found high expression levels of a 6.8-kb RNA transcript in adult heart, brain, placenta, and skeletal muscle, and in fetal lung, liver, and kidney.
Using a combination of cDNA library screening and RACE, Guimera et al. (1999) identified 2 transcription start sites, resulting in MNBHa and MNBHb transcripts. Northern blot analysis of multiple tissues using a probe specific to MNBHa revealed ubiquitous expression, while a probe specific to MNBHb revealed expression only in heart and skeletal muscle. Guimera et al. (1999) also identified at least 4 protein isoforms arising from alternative splicing of the C terminus. All isoforms contain a PEST sequence, which potentially directs rapid degradation of the protein. The most abundant transcript in brain produces the largest isoform (isoform-1), a 763-amino acid protein with a calculated molecular mass of about 85.6 kD. This isoform also contains a histidine repeat and a serine/threonine domain not found in the other isoforms. Guimera et al. (1999) determined that the MNBH variant reported by Shindoh et al. (1996) is 9 amino acids shorter than isoform-1 near the N terminus and results from the use of an alternative splice acceptor site.
Lee et al. (2016) reported that DYRK1A and DYRK1B (604556) kinases phosphorylate ID2 (600386) on threonine-27 (thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (EGLN2; 606424). ID2 binds to the VHL (608537) ubiquitin ligase complex, displaces VHL-associated cullin-2 (603135), and impairs HIF2-alpha (603349) ubiquitylation and degradation. Phosphorylation of thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2-alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2-alpha activity. Conversely, elevated expression of DYRK1 phosphorylates thr27 of ID2, leading to HIF2-alpha destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma.
Guimera et al. (1999) determined that the MNBH gene contains 17 alternatively spliced exons and spans 150 kb. The 5-prime untranslated region contains 2 separate promoters. One promoter, utilized by the MNBHa variant, contains a GC-rich element and no canonic TATA or CAAT boxes. The other, utilized by MNBHb, contains a CAAT box and a nonconsensus AT-rich motif.
Using fluorescence in situ hybridization and regional mapping data, Song et al. (1996) localized the DYRK gene between markers D21S336 and D21S337 in the 21q22.2 region. With amplification by PCR and hybridization analysis, Chen and Antonarakis (1997) mapped the human MNB gene on YACs located on 21q22.2.
Song et al. (1997) mapped the murine Dyrk gene to distal mouse chromosome 16, in agreement with the mapping of human DYRK to a syntenic region of chromosome 21.
Kelly and Rahmani (2005) found that overexpression of human DYRK1A in PC12 rat pheochromocytoma cells potentiated their neuronal differentiation in response to nerve growth factor (see NGFB; 162030). Differentiation required upregulation of the Ras (HRAS; 190020)/MAP kinase (see MAPK1; 176948) signaling pathway, but was independent of DYRK1A kinase activity. DYRK1A prolonged Erk (see MAPK3; 601795) activation by interacting with Ras, Braf (164757), and Mek1 (MAP2K1; 176872) to facilitate formation of a Ras/Braf/Mek1 multiprotein complex.
Using rat hippocampal and mouse neoblastoma cell lines, Kim et al. (2006) found that Dyrk1a interacted with alpha-synuclein (SNCA; 163890), a component of Lewy bodies, one of the pathologic hallmarks of Parkinson disease (168600), Alzheimer disease (104300), and Lewy-body dementia (127750). Dyrk1a serine phosphorylated alpha-synuclein, and this phosphorylation facilitated its intracytoplasmic aggregation.
Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A, that lie within the Down syndrome (190685) critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 were consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease.
In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (114180)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; 600505), and glycogen synthase kinase-3 (GSK3; see 605004). Gwack et al. (2006) used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, Gwack et al. (2006) identified DYRKs as novel regulators of NFAT. DYRK1A and DYRK2 (603496) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, Gwack et al. (2006) concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates.
Ryoo et al. (2007) showed that mice overexpressing human DYRK1A had elevated levels of threonine-phosphorylated tau (MAPT; 157140), which is found in insoluble neurofibrillary tangles in Alzheimer disease brains. DYRK1A phosphorylated tau on threonine and serine residues in vitro. Phosphorylation of tau by DYRK1A reduced the ability of tau to promote microtubule assembly. Ryoo et al. (2007) concluded that an extra copy of DYRK1A can contribute to early onset of Alzheimer disease.
Using a transchromosomic mouse model of Down syndrome, Canzonetta et al. (2008) showed that a 30 to 60% reduced expression of NRSF/REST (600571), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, Canzonetta et al. (2008) mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A. The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. Canzonetta et al. (2008) found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (607937) and Sox2 (184429), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (600576) and a strongly reduced neuroectodermal progenitor compartment. Canzonetta et al. (2008) concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and new rationales for therapeutic approaches.
By varying Dyrk1a gene dosage in mice, Laguna et al. (2008) showed that variations in Dyrk1a expression in retina led to a dose-dependent increase in retinal inner cell number and altered retinal activity. Inner retinal cells were generated normally in mice under- or overexpressing Dyrk1a; however, overexpression of Dyrk1a resulted in inhibitory threonine phosphorylation of caspase-9 (CASP9; 602234), leading to reduced apoptosis and increased cell number.
Baek et al. (2009) demonstrated that DSCR1 expression is increased in Down syndrome tissues and in a mouse model of Down syndrome. Furthermore, the modest increase in expression afforded by a single extra transgenic copy of Dscr1 in mice is sufficient to confer significant suppression of tumor growth, and such resistance is a consequence of a deficit in tumor angiogenesis arising from suppression of the calcineurin pathway. Baek et al. (2009) also provided evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. Baek et al. (2009) concluded that their data provided a mechanism for the reduced cancer incidence of Down syndrome and identified the calcineurin signaling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancer arising in all individuals.
Scales et al. (2009) found that Dyrk1a phosphorylated Map1b (157129) at S1392 to prime Map1b for subsequent phosphorylation by Gsk3-beta (GSK3B; 605004) at S1388 in cultured rat embryonic cortical neurons. Further analysis demonstrated that Dyrk1a-primed and nonprimed Gsk3-beta phosphorylation sites were involved in regulation of microtubule stability in growing cortical neuronal axons.
In a woman with autosomal dominant intellectual developmental disorder-7 (MRD7; 614104), microcephaly, and dysmorphic features, van Bon et al. (2011) identified a de novo heterozygous 52-kb deletion in the DYRK1A gene (600855.0001). This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene. The report supported a role for DYRK1A in human brain development and showed that haploinsufficiency of DYRK1A can cause a distinctive clinical syndrome with mental retardation, primary microcephaly, intrauterine growth retardation, facial dysmorphism, impaired motor functioning, and behavioral problems.
O'Roak et al. (2012) identified 3 de novo mutations in DYRK1A, 2 frameshift and 1 splice site mutation (600855.0002-600855.0004), among 44 candidate gene sequences in 2,446 autism spectrum disorder probands. The 3 patients with DYRK1A mutations had microcephaly relative to individuals screened without DYRK1A mutations (2-sample permutation test, 2-sided p = 0.0005), and the head sizes of these patients was smaller than those of their parents.
Moller et al. (2008) reported 2 unrelated patients with microcephaly, intrauterine growth retardation, postnatal feeding difficulties, and dysmorphic facial features (see 614104) who each had a de novo balanced translocation disrupting the DYRK1A gene: t(9;21)(p12;q22) and t(2;21)(q22;q22), respectively. In the second patient, the 2q22 breakpoint was within intron 39 of the LRP1B (608766) gene. The first child, 24 months old at the time of the report, had large low-set ears, long philtrum, micrognathia, hypogenesis of the corpus callosum, mild developmental delay, and febrile seizures. The second child, age 10 years, had large ears, flat philtrum, asymmetric head, febrile seizures, severe mental retardation, no speech development, and a small ventricular septal defect. Moller et al. (2008) noted the phenotypic similarities to patients with partial monosomy 21 (Matsumoto et al., 1997) and suggested that haploinsufficiency of the DYRK1A gene results in microcephaly as well as other neurodevelopmental anomalies. Van Bon et al. (2011) noted that their patient clearly resembles the 2 patients reported by Moller et al. (2008).
Courcet et al. (2012) reported a 4-year-old child with poor growth, microcephaly (-6 SD), severe mental retardation, seizures, facial dysmorphism, and behavioral abnormalities associated with a de novo heterozygous 69-kb deletion of chromosome 21q22.13 including the 5-prime region of the DYRK1A gene. She had feeding difficulties in infancy, hypotonia, delayed walking, and delayed speech. Facial features included thick lips, bulbous nose, mild hypotelorism, micrognathia, prominent incisors, and large ears with a thick helix. Brain MRI was normal.
Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) identified a total of 212 regions containing putative selective sweeps. Mutations in several genes in regions of selective sweeps, including DYRK1A, NRG3 (605533), CADPS2 (609978), and AUTS2 (607270), have been associated with disorders affecting cognitive capacities. Green et al. (2010) hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.
Jiang et al. (2013) tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, X inactivation-specific transcript (XIST; 314670). Using genome editing with zinc finger nucleases, Jiang et al. (2013) inserted a large inducible XIST transgene into the DYRK1A locus on chromosome 21 in Down syndrome pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. Jiang et al. (2013) suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy.
Using Down syndrome as a model for complex trait analysis, Smith et al. (1997) sought to identify loci from 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. They generated low-copy number transgenic mice, containing 4 different YACs that together cover approximately 2 Mb of contiguous DNA from 21q22.2. They subjected independent mouse lines derived from each of these YAC transgenes to a series of behavioral and learning assays. Two of the 4 YACs caused defects in learning and memory in the transgenic animals, while the other 2 YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region was found to contain the human homolog of the Drosophila 'minibrain' gene, and strongly implicated it in learning defects associated with Down syndrome.
Altafaj et al. (2001) generated transgenic mice overexpressing the full-length cDNA of Dyrk1A. Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. Altafaj et al. (2001) suggested a causative role of DYRK1A in mental retardation and in motor anomalies of Down syndrome.
By gene targeting, Fotaki et al. (2002) created Dyrk1a-null mice. Homozygous null mutants presented a general growth delay and died during midgestation. Heterozygous mice showed decreased neonatal viability and reduced body size from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay in heterozygous mice and specific alterations in adults. Brains of heterozygous mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction.
Using an adeno-associated virus construct that included a small hairpin RNA directed against Dyrk1a, Ortiz-Abalia et al. (2008) downregulated expression of Dyrk1a in transgenic mice overexpressing Dyrk1a as a Down syndrome model. The treatment was devoid of toxicity and normalized Dyrk1a protein levels. Importantly, downregulation of Dyrk1a reversed the corticostriatal-dependent phenotype, as shown by attenuation of hyperactive behavior, restoration of motor-coordination defects, and improved sensorimotor gating.
Lepagnol-Bestel et al. (2009) used the transgenic 152F7 mouse model of Down syndrome to show that DYRK1A gene dosage imbalance deregulated chromosomal clusters of genes located near REST REST/NRSF (600571) binding sites. Dyrk1a bound the SWI/SNF complex, which is known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam (308840) modified the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbed Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. In transgenic embryonic brain subregions, the authors identified a coordinated deregulation of multiple genes that responsible for dendritic growth impairment. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. Lepagnol-Bestel et al. (2009) proposed that both the DYRK1A overexpression-related neuronal gene deregulation (via disturbance of REST/NRSF levels) and the REST/NRSF-SWI/SNF chromatin remodeling complex significantly contribute to the neural phenotypic changes that characterize Down syndrome.
In a woman with intellectual developmental disorder-7 (MRD7; 614104), microcephaly, and dysmorphic features, van Bon et al. (2011) identified a de novo heterozygous 52-kb deletion (chr21:37,796,500-37,849,000, NCBI36) of the DYRK1A gene, affecting the last 3 exons. as an infant, she had failure to thrive, abnormal movements, hypoactivity, and febrile seizures. Brain MRI at age 25 showed a mildly atrophic brain without structural abnormalities. Dysmorphic features included bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. This patient was identified among a larger group of 3,009 mentally retarded individuals studied for copy number variations in the DYRK1A gene.
In a 96-month-old non-Hispanic white male diagnosed with autism and mental retardation (MRD7; 614104), O'Roak et al. (2012) identified a de novo heterozygous 2-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ile48LysfsTer2). The patient's verbal IQ was 63; nonverbal IQ, 55; and low adaptive score, 74. He had polydactyly and had been hypotonic and lethargic as an infant. He was diagnosed with mild mental retardation and found to be excessively clumsy and uncoordinated. His head circumference was 47.6 cm (z score = -3.8). The patient's father and mother were 55 and 39 years of age, respectively, at the time of his conception. His 13-year-old brother was healthy with a normal head circumference.
In a 13-year-old non-Hispanic white female with autism and severe mental retardation (MRD7; 614104), O'Roak et al. (2012) identified a heterozygous de novo splice site mutation in the DYRK1A gene, a G-to-A transition at the 1098+1 position (1098G-A+1). The mutation occurs in the serine/threonine kinase domain. The patient's verbal IQ was 26, nonverbal IQ 42, and adaptive score 41. MRI was normal, but EEG results were unclear. The patient's head circumference was 51.5 cm (z score = -1.6). Her father was 37 at the time of conception and had some evidence of broader autism phenotype with elevated rigid and aloof behaviors.
In a 71-month-old non-Hispanic white male diagnosed with autism (MRD7; 614104), O'Roak et al. (2012) identified a heterozygous de novo 1-bp deletion in the DYRK1A gene that resulted in a frameshift and premature termination of the protein (Ala498ProfsTer94). The patient had a verbal IQ of 91, nonverbal IQ of 66, and adaptive score of 68. He had a history of speech delay and seizures both febrile and nonfebrile, and had ADHD. His head circumference was 48 cm (z score = -2.7). His father was 37 at the time of conception; his mother was 36. Both were healthy with normal head circumferences.
In a 14-year-old girl with severe mental retardation (MRD7; 614104), Courcet et al. (2012) identified a de novo heterozygous 2-bp deletion (290_291delCT) in exon 3 of the DYRK1A gene, resulting in a frameshift and premature termination (Ser97CysfsTer98). The patient had a history of intrauterine growth retardation and feeding difficulties. She developed seizures of multiple types at age 18 months. Other features included microcephaly (-6 SD), severe speech delay, diffuse cortical atrophy on MRI, hand stereotypies, and facial dysmorphism with thick lower lip, mild hypotelorism, and hypoplastic earlobes. This patient was ascertained from a larger cohort of 150 patients with a similar phenotype; she was the only one who had a mutation in the DYRK1A gene.
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