Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants

ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

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Germline de novo variants in CSNK2B in Chinese patients with epilepsy

Scientific Reports ◽

10.1038/s41598-019-53484-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Jinliang Li ◽

Kai Gao ◽

Shuying Cai ◽

Yin Liu ◽

Yuzhen Wang ◽

...

Keyword(s):

De Novo ◽

Clonic Seizure ◽

Binding Domain ◽

Zinc Binding ◽

Chinese Patients ◽

Seizure Onset ◽

Initial Report ◽

Pathogenic Variants ◽

Zinc Binding Domain ◽

Patients With Epilepsy

AbstractCSNK2B, which encodes the beta subunit of casein kinase II (CK2), plays an important role in neuron morphology and synaptic transmission. Variants in CSNK2B associated with epilepsy and/or intellectual disability (ID)/developmental delay (DD) have been reported in five cases only. Among the 816 probands suspected hereditary epilepsy whose initial report of trio-based whole exome sequencing (WES) were negative, 10 de novo pathogenic or likely pathogenic variants of CSNK2B in nine probands were identified after reanalysis of their raw Trio-WES data. Six of the nine epileptic patients had ID/DD. The age of seizure onset of these nine patients with CSNK2B variants ranged from 2–12 months. Eight patients had age of seizure onset of less than 6 months. The epilepsy of most probands (8/9) was generalized tonic-clonic seizure and clustered (6/9). Most patients had normal electroencephalogram (5/9) and brain magnetic resonance image (7/9) results. Most patients (7/9) had easy-to-control seizures. Levetiracetam was the most commonly used drug in seizure-free patients (5/7). The variants detected in five patients (5/9, 55.6%) were located in the zinc-binding domain. In summary, our research provided evidence that variants in CSNK2B are associated with epilepsy with or without ID/DD. CSNK2B-related epilepsy is relatively easy to be controlled. The zinc-binding domain appears to be the hotspot region for mutation.

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Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

10.1101/2020.08.24.20179085 ◽

2020 ◽

Author(s):

Riccardo Sangermano ◽

Iris Deitch ◽

Virginie G Peter ◽

Rola Ba-Abbad ◽

Emily M Place ◽

...

Keyword(s):

Retinal Degeneration ◽

Early Onset ◽

Joubert Syndrome ◽

Phenotypic Correlation ◽

Cone Dystrophy ◽

Genetic Modifiers ◽

Retinal Degenerations ◽

Pathogenic Variants ◽

Systemic Disorder ◽

The Impact

Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

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Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

Neurology Genetics ◽

10.1212/nxg.0000000000000206 ◽

2017 ◽

Vol 3 (6) ◽

pp. e206 ◽

Cited By ~ 21

Author(s):

Carla Marini ◽

Michele Romoli ◽

Elena Parrini ◽

Cinzia Costa ◽

Davide Mei ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Focal Epilepsy ◽

Brain Mri ◽

Somatic Mosaicism ◽

Epileptic Encephalopathy ◽

Seizure Onset ◽

Severe Intellectual Disability ◽

The Mean

Objective:To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.Methods:Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.Results:The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.Conclusions:KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

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Religiosity and spirituality in patients with epilepsy

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20190055 ◽

2019 ◽

Vol 77 (5) ◽

pp. 335-340

Author(s):

Isadora Barazzetti Rigon ◽

Gabriel de Almeida Calado ◽

Lucas Savaris Linhares ◽

Pietro Lentz Martins Cantu ◽

Jorge Luis Wollstein Moritz ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Depression Scale ◽

Religious Experiences ◽

Epileptic Syndromes ◽

The Mean ◽

Religiosity And Spirituality ◽

Patients With Epilepsy ◽

The Impact

ABSTRACT Religiosity and spirituality (R/S) are widely regarded as important allies against illness and suffering in general. Findings in temporal lobe epilepsy (TLE) suggest the temporal lobe as the anatomical-functional basis of religious experiences. Both R/S are relevant in patients with epilepsy (PWE) since epilepsy can lead to psychosocial issues for a significant portion of patients and their families. Objective: To investigate R/S in PWE, as well as the impact of different epileptic syndromes on patients' R/S. Methods: One hundred PWE and 50 healthy volunteers matched for age, sex and educational level were submitted to an interview, as well as three previously validated questionnaires: Index of Core Spiritual Experience (INSPIRIT-R), Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Results: PWE's and control's mean ages were 35.9 ± 12.4 vs. 36.3 ± 18.1 years, mean schooling was 8.9 ± 3.7 vs. 10.1 ± 4.2 years. The mean age of epilepsy onset was 14.5 ± 12.1 and monthly frequency of seizures was 5.9 ± 12.6. INSPIRIT-R's scores were not statistically significantly different between patients and controls (3.0 ± 0.8 vs. 3.0 ± 0.8); however, INSPIRIT-R's scores were significantly higher in TLE patients when compared with other epilepsy syndromes (3.2 ± 0.7 vs. 2.8 ± 0.9; p = 0.04). Conclusion: Temporal lobe epilepsy patients have higher levels of R/S.

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CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants

BMC Medical Genomics ◽

10.1186/s12920-021-01033-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Leigh Ann Higa ◽

Jennifer Wardley ◽

Christopher Wardley ◽

Susan Singh ◽

Timothy Foster ◽

...

Keyword(s):

Developmental Delay ◽

Sleep Disturbances ◽

Right Hemisphere ◽

De Novo ◽

Autism Spectrum ◽

Loss Of Function ◽

Seizure Onset ◽

Genomic Deletions ◽

Functional Studies ◽

Pathogenic Variants

Abstract Background Pathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published. Case presentation We identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2. Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions. Conclusions This expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

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Interpreting short tandem repeat variations in humans using mutational constraint

10.1101/092734 ◽

2016 ◽

Cited By ~ 2

Author(s):

Melissa Gymrek ◽

Thomas Willems ◽

David Reich ◽

Yaniv Erlich

Keyword(s):

Tandem Repeats ◽

De Novo ◽

Analytical Framework ◽

Robust Estimates ◽

Pathogenic Variants ◽

Bioinformatics Tools ◽

Local Sequence ◽

Human Disorders ◽

The Impact ◽

Short Tandem

AbstractIdentifying regions of the genome that are depleted of mutations can reveal potentially deleterious variants. Short tandem repeats (STRs), also known as microsatellites, are among the largest contributors of de novo mutations in humans and are implicated in a variety of human disorders. However, because of the challenges STRs pose to bioinformatics tools, per-locus studies of STR mutations have been limited to highly ascertained panels of several dozen loci. Here, we harnessed bioinformatics tools and a novel analytical framework to estimate mutation parameters for each STR in the human genome by correlating STR genotypes with local sequence heterozygosity. We applied our method to obtain robust estimates of the impact of local sequence features on mutation parameters and used this to create a framework for measuring constraint at STRs by comparing observed vs. expected mutation rates. Constraint scores identified known pathogenic variants with early onset effects. Our constraint metrics will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies.

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Genetic Paths to Evolutionary Rescue and the Distribution of Fitness Effects Along Them

Genetics ◽

10.1534/genetics.119.302890 ◽

2019 ◽

Vol 214 (2) ◽

pp. 493-510 ◽

Cited By ~ 5

Author(s):

Matthew M. Osmond ◽

Sarah P. Otto ◽

Guillaume Martin

Keyword(s):

Genetic Basis ◽

De Novo ◽

Geometric Model ◽

Past Century ◽

Single Mutation ◽

Theoretical Inquiry ◽

Evolutionary Rescue ◽

Declining Populations ◽

Asexual Populations ◽

The Impact

The past century has seen substantial theoretical and empirical progress on the genetic basis of adaptation. Over this same period, a pressing need to prevent the evolution of drug resistance has uncovered much about the potential genetic basis of persistence in declining populations. However, we have little theory to predict and generalize how persistence—by sufficiently rapid adaptation—might be realized in this explicitly demographic scenario. Here, we use Fisher’s geometric model with absolute fitness to begin a line of theoretical inquiry into the genetic basis of evolutionary rescue, focusing here on asexual populations that adapt through de novo mutations. We show how the dominant genetic path to rescue switches from a single mutation to multiple as mutation rates and the severity of the environmental change increase. In multi-step rescue, intermediate genotypes that themselves go extinct provide a “springboard” to rescue genotypes. Comparing to a scenario where persistence is assured, our approach allows us to quantify how a race between evolution and extinction leads to a genetic basis of adaptation that is composed of fewer loci of larger effect. We hope this work brings awareness to the impact of demography on the genetic basis of adaptation.

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Wolfram-like syndrome – another face of a rare disease in children

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0348 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Mariusz Smetek ◽

Karolina Gadzalska ◽

Paulina Jakiel ◽

Julia Grzybowska ◽

Malgorzata Mysliwiec ◽

...

Keyword(s):

De Novo ◽

Insulin Dependent Diabetes Mellitus ◽

Wolfram Syndrome ◽

Dependent Diabetes Mellitus ◽

Single Mutation ◽

Pathogenic Variants ◽

Ophthalmologic Examination ◽

Insulin Dependent ◽

Type 1 Dm

Abstract Objectives The presence of two pathogenic variants in the WFS1 gene leads to the occurrence of a rare genetic disease in children – Wolfram syndrome (WFS), which includes insulin-dependent diabetes mellitus (DM), optic atrophy (OA), diabetes insipidus (DI), and deafness (D). However, the presence of a single mutation in the WFS1 gene results in a number of other autosomal dominant inherited diseases, including Wolfram-like syndrome (WFS-like). Case presentation A 10-year-old boy was referred to the Genetic Outpatient Clinic with suspected WFS based on the coexistence of D, type 1 DM, short stature, and abnormalities in ophthalmologic examination (astigmatism and OA due to the optical coherence tomography result). The genetic analysis did not confirm WFS syndrome in the boy but identified a single likely pathogenic de novo variant in the WFS1 gene, which confirmed WFS-like syndrome. Conclusions Currently, the patient is under the care of an endocrinologist, diabetologist, ophthalmologist, audiologist, and also psychologist because of mood disorders.

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Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

Frontiers in Neurology ◽

10.3389/fneur.2021.633637 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xianyu Liu ◽

Qiyang Shen ◽

Guo Zheng ◽

Hu Guo ◽

Xiaopeng Lu ◽

...

Keyword(s):

De Novo ◽

Homology Modelling ◽

Epileptic Encephalopathy ◽

Therapeutic Interventions ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Heterozygous Variant ◽

Single Centre Study ◽

Next Generation Sequencing Ngs ◽

The Impact

Objective: The genetic aetiology of epileptic encephalopathy (EE) is growing rapidly based on next generation sequencing (NGS) results. In this single-centre study, we aimed to investigate a cohort of Chinese children with early infantile epileptic encephalopathy (EIEE).Methods: NGS was performed on 50 children with unexplained EIEE. The clinical profiles of children with pathogenic variants were characterised and analysed in detail. Conservation analysis and homology modelling were performed to predict the impact of STXBP1 variant on the protein structure.Results: Pathogenic variants were identified in 17 (34%) of 50 children. Sixteen variants including STXBP1 (n = 2), CDKL5 (n = 2), PAFAH1B1, SCN1A (n = 9), SCN2A, and KCNQ2 were de novo, and one (PIGN) was a compound heterozygous variant. The phenotypes of the identified genes were broadened. PIGN phenotypic spectrum may include EIEE. The STXBP1 variants were predicted to affect protein stability.Significance: NGS is a useful diagnostic tool for EIEE and contributes to expanding the EIEE-associated genotypes. Early diagnosis may lead to precise therapeutic interventions and can improve the developmental outcome.

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The Quality of life among adult Sudanese patients with epilepsy

10.21203/rs.3.rs-646638/v1 ◽

2021 ◽

Author(s):

Amira Siddig ◽

Abbasher Hussien Mohamed Ahmed ◽

Khabab Abbasher Hussien Mohamed Ahmed ◽

Mohammed Eltahier Abdalla Omer

Keyword(s):

Quality Of Life ◽

Demographic Characteristics ◽

Brain Disorder ◽

Item Questionnaire ◽

Considerable Impact ◽

The Mean ◽

Patients With Epilepsy ◽

The Impact ◽

Ilae Classification

Abstract Introduction: Epilepsy is the most common serious brain disorder worldwide, the impact of it on quality of life can be substantial with far-reaching and life-long consequences despite all this very few studies have been carried out on the QOL in epilepsy. Objectives: To investigate the quality of life in adult Sudanese patients with epilepsy attending Daoud charity clinic June to July 2018.Methodology: Thirty six adult Sudanese patients with epilepsy were included in the study, a multi item questionnaire graded scale and check list to explore the demographic characteristics were used to assess the impact of epilepsy on QOL. Respondents were adults aged at least 18 years old with a diagnosis of epilepsy for more than 3 months the unpaired t-test or one way analysis of variances was used to compare means of QOL scores between groups. Results: Out of 360 patients 190 were males and 170 were females, the mean of age was 34.81.The most frequent type of epilepsy according to the ILAE classification was the generalized tonic clonic (78.4% of patients) .40.5% of patients had < 1 seizure per month during last year while 40.5% had more than 1 seizure per month and 16.2% were free of seizure during last year. The mean total score QOLIE-31 of this study was 43.97_+ 4.78 .Sex, age and marital state did not affect QOL scores. The study showed that type of seizure and duration of epilepsy did appear to be predictive of HRQOL .Adverse effects of antiepileptic drugs (AEDs) have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients Conclusion: The decrease in overall score of quality of life in adult Sudanese patients is multifactorial.

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