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 Participants: A 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 Measures: The 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.
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 Participants: A 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 Measures: The 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.
Authors: G McMichael; M N Bainbridge; E Haan; M Corbett; A Gardner; S Thompson; B W M van Bon; C L van Eyk; J Broadbent; C Reynolds; M E O'Callaghan; L S Nguyen; D L Adelson; R Russo; S Jhangiani; H Doddapaneni; D M Muzny; R A Gibbs; J Gecz; A H MacLennan Journal: Mol Psychiatry Date: 2015-02-10 Impact factor: 15.992
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Authors: Sheng Chih Jin; Sara A Lewis; Somayeh Bakhtiari; Xue Zeng; Michael C Sierant; Sheetal Shetty; Sandra M Nordlie; Aureliane Elie; Mark A Corbett; Bethany Y Norton; Clare L van Eyk; Shozeb Haider; Brandon S Guida; Helen Magee; James Liu; Stephen Pastore; John B Vincent; Janice Brunstrom-Hernandez; Antigone Papavasileiou; Michael C Fahey; Jesia G Berry; Kelly Harper; Chongchen Zhou; Junhui Zhang; Boyang Li; Hongyu Zhao; Jennifer Heim; Dani L Webber; Mahalia S B Frank; Lei Xia; Yiran Xu; Dengna Zhu; Bohao Zhang; Amar H Sheth; James R Knight; Christopher Castaldi; Irina R Tikhonova; Francesc López-Giráldez; Boris Keren; Sandra Whalen; Julien Buratti; Diane Doummar; Megan Cho; Kyle Retterer; Francisca Millan; Yangong Wang; Jeff L Waugh; Lance Rodan; Julie S Cohen; Ali Fatemi; Angela E Lin; John P Phillips; Timothy Feyma; Suzanna C MacLennan; Spencer Vaughan; Kylie E Crompton; Susan M Reid; Dinah S Reddihough; Qing Shang; Chao Gao; Iona Novak; Nadia Badawi; Yana A Wilson; Sarah J McIntyre; Shrikant M Mane; Xiaoyang Wang; David J Amor; Daniela C Zarnescu; Qiongshi Lu; Qinghe Xing; Changlian Zhu; Kaya Bilguvar; Sergio Padilla-Lopez; Richard P Lifton; Jozef Gecz; Alastair H MacLennan; Michael C Kruer Journal: Nat Genet Date: 2020-09-28 Impact factor: 41.307
Authors: Oksana Suchowersky; Setareh Ashtiani; Ping-Yee Billie Au; Scott McLeod; Mehrdad A Estiar; Ziv Gan-Or; Guy A Rouleau Journal: Clin Park Relat Disord Date: 2021-11-03
Authors: Maya Chopra; Dustin L Gable; Jamie Love-Nichols; Alexa Tsao; Shira Rockowitz; Piotr Sliz; Elizabeth Barkoudah; Lucia Bastianelli; David Coulter; Emily Davidson; Claudio DeGusmao; David Fogelman; Kathleen Huth; Paige Marshall; Donna Nimec; Jessica Solomon Sanders; Benjamin J Shore; Brian Snyder; Scellig S D Stone; Ana Ubeda; Colyn Watkins; Charles Berde; Jeffrey Bolton; Catherine Brownstein; Michael Costigan; Darius Ebrahimi-Fakhari; Abbe Lai; Anne O'Donnell-Luria; Alex R Paciorkowski; Anna Pinto; John Pugh; Lance Rodan; Eugene Roe; Lindsay Swanson; Bo Zhang; Michael C Kruer; Mustafa Sahin; Annapurna Poduri; Siddharth Srivastava Journal: Ann Clin Transl Neurol Date: 2022-01-24 Impact factor: 4.511