Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy

McMichael, G.; Bainbridge, Matthew N.; Haan, Eric; Corbett, Mark; Gardner, Alison; Thompson, Suzanna C.; Bon, Bregje W.M. van; Eyk, Clare L. van; Broadbent, J. L.; Reynolds, Chandra A.; O’Callaghan, Michael; Nguyen, Lam Son; Adelson, David L.; Russo, Remo; Jhangiani, Shalini N.; Doddapaneni, Harshavardhan; Muzny, Donna M.; Gibbs, Richard A.; Gécz, Jozef; MacLennan, Alastair H.

doi:10.1038/mp.2014.189

Cited by 198 publications

(201 citation statements)

References 47 publications

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“…El 1-2% de las PC (La gran mayoría de origen familiar), han sido ligadas a mutaciones genéticas 20,36 .…”

Section: Introductionunclassified

“…11 G. McMichael y cols. en Australia llevaron a cabo la secuenciación exómica de 183 casos de pacientes con PC incluyendo ambos padres (98 casos), o un solo padre (67 casos) y 18 casos únicos (Sin ADN de los padres) 20 . Se identificaron y validaron de novo 61 variantes proteicas en 46 de los 98 casos de los que se incluyeron ambos padres.…”

Section: Introductionunclassified

“…La mitad fueron en nuevos genes. 20 La heterogeneidad genética pone en contexto la complejidad de la contribución genética en la PC, pero esto no implica que la identificación de estas asociaciones explique la causa de la PC.…”

Section: Introductionunclassified

“…6 La secuenciación exómica y la posibilidad de analizar toda la información genómica, no solo ha permitido investigar pacientes con condiciones clínicas raras y complejas46, sino poder darle una explicación al niño con diagnóstico de parálisis cerebral sin etiología clara que pueda tener asociaciones genéticas, posibilitando el direccionamientos en el estudio de posibles causas etiológicas. En algunos casos logrando agrupar fenotipos de la PC, como ocurre con la PC atáxica, en la cual se ha encontrado genes patógenos relacionados a un grupo de patologías denominado Ataxia Espinocerebelar, con un presentación congénita, de carácter no progresivo47; lo que lleva a cuestionamientos acerca de lo que se conoce como PC, o en realidad estos avances en genética permiten un mayor entendimiento y una mejor clasificación de la Parálisis Cerebral 12,20,47 .…”

Section: Introductionunclassified

“…Y quizás no muy lejos se logre entender la interacción entre la susceptibilidad genética tan heterogénea, con el entorno que involucra al niño aun antes de nacer 16,45,51 , es decir la relación de los hallazgos genéticos encontrados con los factores de riesgo neurológicos que involucran no solo prematurez, sino alimentación 52 , riesgo psicosocial16entre otros aspectos que no solo influyen en la presentación de la PC sino en las comorbilidades que afectan potencialmente el pronóstico y calidad de vida 53 , lo que parece ser la base de este complejo trastorno del neurodesarrollo llamado parálisis cerebral 20,49 .…”

Section: Introductionunclassified

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Asociaciones genéticas en la parálisis cerebral; un campo aún en estudio

Arroyo¹,

Franco²,

Valencia³

2016

Rev Col Med Fis Reh

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“…El 1-2% de las PC (La gran mayoría de origen familiar), han sido ligadas a mutaciones genéticas 20,36 .…”

Section: Introductionunclassified

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Asociaciones genéticas en la parálisis cerebral; un campo aún en estudio

Arroyo¹,

Franco²,

Valencia³

2016

Rev Col Med Fis Reh

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Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Moreno-De-Luca

Millan²,

Pesacreta

et al. 2021

JAMA

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IMPORTANCE Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases.OBJECTIVE To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017.EXPOSURES Exome sequencing with copy number variant detection. MAIN OUTCOMES AND MEASURESThe primary outcome was the molecular diagnostic yield of exome sequencing. RESULTS Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients).CONCLUSIONS AND RELEVANCE Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.

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Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy

et al. 2022

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ImportanceThere are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA).ObjectiveTo synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA.Data SourcesSearched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022).Study SelectionInclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed.Data Extraction and SynthesisPreferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer.Main Outcomes and MeasuresA separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies.ResultsIn the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%).Conclusions and RelevanceResults of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.

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Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy

Cited by 198 publications

References 47 publications

Asociaciones genéticas en la parálisis cerebral; un campo aún en estudio

Asociaciones genéticas en la parálisis cerebral; un campo aún en estudio

Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy

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