Phenotypic cooperation of a KCNQ2 exon 7 partial duplication and compound copy number variations in genes associated to a severe epileptic and neurodevelopmental delay
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PROVIDER: PRJNA505669 | ENA |
REPOSITORIES: ENA
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Project description:A 6-year-old boy, second son of healthy parents affected with epileptic encephalopathy of neonatal onset. Pregnancy with gestational diabetes controlled with diet. Delivery was uneventful. Since 48 hours of life, he presented episodes of cyanosis, generalized hypertonia, and tonic asymmetric postures followed by apnea. Video-EEG at 5 days of life showed bilateral and asynchronous spike-and-wave. Seizures were refractory to phenobarbital but were controlled with phenytoin. Since 3 months of age, he presented with startle episodes without EEG correlate related to the wake and sleep transition together with dystonic postures. One month later, epileptic spasms without hypsarrhythmia were observed. No response to levetiracetam and valproic acid but stopped after lacosamide (LCS) treatment was initiated (11 months of age). Metabolic tests (including CSF studies), karyotype, and brain MRI were normal. Epileptic encephalopathy gene panel was negative including hyperekplexia related genes. Progressive increase of TSH was treated with oral L-t4. At 20 months he presented recurrence of spasms that were controlled with LCS dose adjustment. V-EEG: abnormal background activity and paroxysmal multifocal discharges that showed activation and generalization during sleep. After several years of good seizure control, LCS was discontinued. He suffered from decompensation of seizures with febrile viral infection and at 5 years of age he presented startle episodes associated to auditory stimulus without EEG correlate, but during sleep, he presented epileptic spasms with EEG correlate. Treatment with vigabatrine was initiated with a clinical and EEG improvement. At physical exam he presents severe axial hypotonia without head control. Hypertonia of 4 limbs with dystonic movements of upper limbs. No hand use and is not able to sit or crawl. No development of expressive language.GMFCS: V. No development of expressive language. Last v-EEG monitoring showed bilateral polyspike discharges and clinical spasms in polygraph recording without any clear EEG correlate. Whole exome sequencing was performed and partial exon 7 duplication, heterozygous variant, in KCNQ2 was found. aCGH study detected several CNV in genes associated to neural functions (losses: LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3. Gains : PCDH19, TENM1, EFNA5).
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Project description:Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.
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Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.
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Project description:Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence and impaired adaptive behavior, frequently as well as visual impairments. Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an interacting partner of fragile X mental retardation protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants were found in patients with early-onset epileptic encephalopathy, developmental delay, and ID. Individuals with these CYFIP2 variants often exhibit visual impairments, however, the underlying mechanism is poorly understood. In the current study, we investigated the role of Cyfip2 in retinal and visual function by generating and analyzing mice in which Cyfip2 is depleted in the retina (Cyfip2 CKO mice). We found no major difference in the layer structure and cell composition between control and Cyfip2 CKO retinas, whereas a subset of genes associated with transporter and channel activity was differentially expressed in the Cyfip2 CKO retina. Multi-electrode array recordings showed more sustained and stronger response to positive flashes of ON ganglion cells in the Cyfip2 CKO retina, although we did not observe that Cyfip2 deficiency affects photoreceptor and ON bipolar cell functions by electroretinogram analysis. Furthermore, initial and late phase OKR analysis demonstrated that Cyfip2 deficiency impairs visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders including ID.
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