scholarly journals Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

2021 ◽  
Vol 12 ◽  
Author(s):  
Diane Beysen ◽  
Chania De Cordt ◽  
Charlotte Dielman ◽  
Benson Ogunjimi ◽  
Julie Dandelooy ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Genetic Testing ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Birth Asphyxia ◽  
Spastic Cerebral Palsy

Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation.

scholarly journals ESHRE PGT Consortium good practice recommendations for the organisation of PGT†

2020 ◽  
Vol 2020 (3) ◽  
Author(s):  
Filipa Carvalho ◽  
Edith Coonen ◽  
Veerle Goossens ◽  
Georgia Kokkali ◽  
Carmen Rubio ◽  
...  
Keyword(s):  
Best Practice ◽  
Single Gene ◽  
Good Practice ◽  
Diagnostic Testing ◽  
Genetic Diagnosis ◽  
Information Provision ◽  
Embryo Biopsy ◽  
Preimplantation Genetic Testing ◽  
Gene Defects

Abstract The field of preimplantation genetic testing (PGT) is evolving fast, and best practice advice is essential for regulation and standardisation of diagnostic testing. The previous ESHRE guidelines on best practice for preimplantation genetic diagnosis, published in 2005 and 2011, are considered outdated and the development of new papers outlining recommendations for good practice in PGT was necessary. The current updated version of the recommendations for good practice is, similar to the 2011 version, split into four documents, one of which covers the organisation of a PGT centre. The other documents focus on the different technical aspects of embryo biopsy, PGT for monogenic/single-gene defects (PGT-M) and PGT for chromosomal structural rearrangements/aneuploidies (PGT-SR/PGT-A). The current document outlines the steps prior to starting a PGT cycle, with details on patient inclusion and exclusion, and counselling and information provision. Also, recommendations are provided on the follow-up of PGT pregnancies and babies. Finally, some further recommendations are made on the practical organisation of an IVF/PGT centre, including basic requirements, transport PGT and quality management. This document, together with the documents on embryo biopsy, PGT-M and PGT-SR/PGT-A, should assist everyone interested in PGT in developing the best laboratory and clinical practice possible.

scholarly journals Rapid protocol for pre-conception genetic diagnosis of single gene mutations by first polar body analysis: a possible solution for the Italian patients

2007 ◽  
Vol 28 (1) ◽  
pp. 62-64 ◽  
Author(s):  
F. Fiorentino ◽  
A. Biricik ◽  
A. Nuccitelli ◽  
R. De Palma ◽  
S. Kahraman ◽  
...  
Keyword(s):  
Single Gene ◽  
Polar Body ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
First Polar Body ◽  
Polar Body Analysis

scholarly journals Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2303-2318 ◽  
Author(s):  
Joseph D Symonds ◽  
Sameer M Zuberi ◽  
Kirsty Stewart ◽  
Ailsa McLellan ◽  
Mary O‘Regan ◽  
...  
Keyword(s):  
Early Childhood ◽  
Genetic Testing ◽  
Confidence Interval ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Population Based ◽  
Childhood Onset ◽  
Live Births ◽  
Precision Therapy ◽  
Genetic Epilepsies

Abstract Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism

2020 ◽  
Vol 21 ◽  
Author(s):  
Aarti Tiwari ◽  
Saloni Rahi ◽  
Sidharth Mehan
Keyword(s):  
Autism Spectrum Disorder ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Erk Signaling ◽  
Erk Pathway ◽  
Signaling Mechanism ◽  
Syndromic Autism

Abstract: Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chro-mosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized pri-marily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has re-cently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addi-tion, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder

Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

2020 ◽  
pp. 1-12
Author(s):  
So Lee ◽  
Natalya Karp ◽  
Eugenio Zapata-Aldana ◽  
Bekim Sadikovic ◽  
Ping Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Diagnostic Yield ◽  
Single Gene ◽  
Medication Management ◽  
Genetic Diagnosis ◽  
Single Center Experience ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
Patients With Epilepsy

ABSTRACT: Background: Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children’s Hospital, London, Ontario, Canada. Methods: Children (birth–18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008–March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. Results: In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Conclusions: Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province.

scholarly journals Clinical utility of genetic testing in the precision management of pediatric patients with kidney disease

Kidney360 ◽  
2020 ◽  
pp. 10.34067/KID.0002272020
Author(s):  
Nasim Bekheirnia ◽  
Kevin E. Glinton ◽  
Linda Rossetti ◽  
Joshua Manor ◽  
Wuyan Chen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Kidney Disease ◽  
Clinical Laboratory ◽  
Diagnostic Yield ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Chromosomal Microarray ◽  
Wide Range

Background: As genetic testing increasingly integrates into the practice of nephrology, our understanding of the basis of many kidney disorders has exponentially increased. Given this, we recently initiated a Renal Genetics Clinic (RGC) at our large, urban children's hospital for patients with kidney disorders. Methods: Genetic testing was performed in Clinical Laboratory Improvement Amendments (CLIA) certified laboratories using single gene testing, multi-gene panels, chromosomal microarray (CMA), or exome sequencing (ES). Results: A total of 192 patients were evaluated in this clinic, with cystic kidney disease (49/192) being the most common reason for referral followed by Congenital Anomalies of the Kidney and Urinary Tract (CAKUT: 41/192) and hematuria (38/192). Genetic testing was performed for 158 patients with an overall diagnostic yield of 81/158 (51.3%). In the patients who reached a genetic diagnosis, 16/81 (19.7%), medical or surgical treatment of the patients were impacted, and in 12/81 (14.8%), previous clinical diagnoses were changed to more accurate genetic diagnoses. Conclusions: Such testing provided an accurate diagnosis for children and in some cases led to further diagnosis in seemingly asymptomatic family members and changes to overall medical management. Genetic testing, as facilitated by such a specialized clinical setting, thus appears to have clear utility in the diagnosis and counseling of patients with a wide range of kidney manifestations.

scholarly journals Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Neil V Morgan ◽  
Bryndis Yngvadottir ◽  
Mary O’Driscoll ◽  
Graeme R Clark ◽  
Diana Walsh ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Neurological Disease ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Disease Status ◽  
Missense Variant ◽  
Spastic Cerebral Palsy ◽  
Single Family ◽  
Loss Of Function ◽  
Candidate Mutation

Abstract A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.

scholarly journals A STUDY OF NEONATES WITH BIRTH ASPHYXIA FOR SEQUELAE OVER 2 YEARS

2019 ◽  
Vol 3 (6) ◽  
Author(s):  
Dr. Y. Vamseedhar ◽  
Dr. B.K. Niranjan
Keyword(s):  
Carbon Dioxide ◽  
Cerebral Palsy ◽  
Arterial Oxygen Tension ◽  
Birth Asphyxia ◽  
Glucose Production ◽  
Hypoxic Ischemic Encephalopathy ◽  
Arterial Oxygen ◽  
Spastic Cerebral Palsy ◽  
Increased Risk ◽  
Ischemic Encephalopathy

Introduction: Birth asphyxia is associated with reduction in the arterial oxygen tension, accumulation of carbon dioxide and fall in blood pH. Acidosis occurs due to anerobic utilization of glucose, production of lactic acid and accumulation of carbon dioxide. Aim: To study outcome of neonates who suffered birth asphyxia and Hypoxic–ischemic encephalopathy (HIE) in a teaching hospital over a period of 2 years. Materials & Methods: 325 neonates with birth asphyxia and hypoxic ischemic encephalopathy were studied, with well defined inclusion and exclusion criteria. They were treated according to standard protocols. Observations : 106 neonates of HIE-I, 58 neonates of HIE-II, and 59 neonates of HIE-III were followed up: for various outcomes like death due to complications, cerebral palsy, developmental delay with epilepsy, hearing handicap etc. Results: In HIE-I no case progressed to cerebral palsy, in HIE-II 24.13% progressed into CP and in HIE-III 54.2% developed spastic cerebral palsy. Conclusion: Infants with severe grades of HIE have increased risk of long term neurological sequlae. Keywords: Neonate, Birth asphyxia, Acidosis, Neonatal encephalopathy

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