scholarly journals Gene and Phenotype Expansion of Unexplained Early Infantile Epileptic Encephalopathy

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.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

2022 ◽  
pp. 097321792110688
Author(s):  
Francisco Ribeiro-Mourão ◽  
Ana Vilan ◽  
Sara Passos-Silva ◽  
Fernando Silveira ◽  
Miguel Leão ◽  
...  
Keyword(s):  
De Novo ◽  
Bone Fractures ◽  
Muscular Atrophy ◽  
Hip Dislocation ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
Genetic Abnormalities ◽  
Heterozygous Variant ◽  
Fetal Movements ◽  
Intrafamilial Variability

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

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

2020 ◽  
Vol 6 (6) ◽  
pp. e528
Author(s):  
Federica Malerba ◽  
Giulio Alberini ◽  
Ganna Balagura ◽  
Francesca Marchese ◽  
Elisabetta Amadori ◽  
...  
Keyword(s):  
De Novo ◽  
Cognitive Outcome ◽  
Single Mutation ◽  
Genetic Modifiers ◽  
Seizure Onset ◽  
Pathogenic Variants ◽  
Intellectual Outcome ◽  
The Mean ◽  
Patients With Epilepsy ◽  
The Impact

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.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

scholarly journals Mutations in both SAMD9 and SLC19A2 genes caused complex phenotypes characterized by recurrent infection, dysphagia and profound deafness – a case report for dual diagnosis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yan Zhang ◽  
Yi Zhang ◽  
Victor Wei Zhang ◽  
Chunyi Zhang ◽  
Hongke Ding ◽  
...  
Keyword(s):  
De Novo ◽  
Vitamin B1 ◽  
Recurrent Infection ◽  
Multiple Organ ◽  
Growth Delay ◽  
Compound Heterozygous ◽  
Mendelian Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Low Incidence

Abstract Background Phenotypic difference is general in Mendelian disease. Due to the extremely low incidence for a single disease, phenotype spectrum needs to be expanded. Meanwhile, earlier knowledge says patients who suffered from two kinds of different Mendelian disease are very rare. Case presentation We describe a case of neonatal male with genital anomalies, growth delay, skin hyperpigmentation, chronic lung disease with recurrent infection, anemia, and severe deafness. Without any clear etiology after routine workflow, whole exome sequencing was carried on. A pathogenic de novo SAMD9 mutation and compound heterozygous likely-pathogenic variants in SLC19A2 were identified. Some symptoms were improved after the patient was treated with vitamin B1. Unfortunately, the boy died from sepsis and multiple organ failure before 1 year old. Conclusion Combining the phenotype and clinical progress of treatment, we report that it is the first case of a patient with both MIRAGE syndrome and TRMA syndrome.

scholarly journals De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

2018 ◽  
Vol 103 (5) ◽  
pp. 666-678 ◽  
Author(s):  
Katherine L. Helbig ◽  
Robert J. Lauerer ◽  
Jacqueline C. Bahr ◽  
Ivana A. Souza ◽  
Candace T. Myers ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variants

STXBP1 encephalopathy

Neurology ◽  
2019 ◽  
Vol 93 (3) ◽  
pp. 114-123 ◽  
Author(s):  
Vanessa Lanoue ◽  
Ye Jin Chai ◽  
Julie Z. Brouillet ◽  
Sarah Weckhuysen ◽  
Elizabeth E. Palmer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neural Development ◽  
Early Onset ◽  
De Novo ◽  
Basic Research ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Severe Form ◽  
Pathogenic Variants ◽  
Extrapyramidal Features

De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

scholarly journals De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Robin N. Stringer ◽  
Bohumila Jurkovicova-Tarabova ◽  
Ivana A. Souza ◽  
Judy Ibrahim ◽  
Tomas Vacik ◽  
...  
Keyword(s):  
Ion Channel ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Whole Exome ◽  
Heterozygous Variant

AbstractDevelopmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

scholarly journals ‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

2020 ◽  
Vol 182 (1) ◽  
pp. K1-K6 ◽  
Author(s):  
Yunting Lin ◽  
Yanna Cai ◽  
Jianan Xu ◽  
Chunhua Zeng ◽  
Huiying Sheng ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Hypophosphatemic Rickets ◽  
Dominant Inheritance ◽  
Germline Mosaicism ◽  
Pathogenic Variants ◽  
First Case ◽  
Heterozygous Variant ◽  
The Family ◽  
Normal Father

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

scholarly journals Molecular and Genetic Mechanism of Non-Syndromic Congenital Cataracts. Mutation Screening in Spanish Families

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 580
Author(s):  
Celia Fernández-Alcalde ◽  
María Nieves-Moreno ◽  
Susana Noval ◽  
Jesús M. Peralta ◽  
Victoria E. F. Montaño ◽  
...  
Keyword(s):  
De Novo ◽  
Mutation Screening ◽  
Disease Genes ◽  
De Novo Mutations ◽  
Congenital Cataracts ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Almost All ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Our purpose was to identify mutations responsible for non-syndromic congenital cataracts through the implementation of next-generation sequencing (NGS) in our center. A sample of peripheral blood was obtained from probands and willing family members and genomic DNA was extracted from leukocytes. DNA was analyzed implementing a panel (OFTv2.1) including 39 known congenital cataracts disease genes. 62 probands from 51 families were recruited. Pathogenic or likely pathogenic variants were identified in 32 patients and 25 families; in 16 families (64%) these were de novo mutations. The mutation detection rate was 49%. Almost all reported mutations were autosomal dominant. Mutations in crystallin genes were found in 30% of the probands. Mutations in membrane proteins were detected in seven families (two in GJA3 and five in GJA8). Mutations in LIM2 and MIP were each found in three families. Other mutations detected affected EPHA2, PAX6, HSF4 and PITX3. Variants classified as of unknown significance were found in 5 families (9.8%), affecting CRYBB3, LIM2, EPHA2, ABCB6 and TDRD7. Mutations lead to different cataract phenotypes within the same family.

Sign in / Sign up

Export Citation Format

Share Document