Dataset Information

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

ABSTRACT:

Objectives

Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP.

Methods

We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline.

Results

We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES.

Interpretation

WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.

SUBMITTER: Chopra M

PROVIDER: S-EPMC8862420 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

Chopra Maya M Gable Dustin L DL Love-Nichols Jamie J Tsao Alexa A Rockowitz Shira S Sliz Piotr P Barkoudah Elizabeth E Bastianelli Lucia L Coulter David D Davidson Emily E DeGusmao Claudio C Fogelman David D Huth Kathleen K Marshall Paige P Nimec Donna D Sanders Jessica Solomon JS Shore Benjamin J BJ Snyder Brian B Stone Scellig S D SSD Ubeda Ana A Watkins Colyn C Berde Charles C Bolton Jeffrey J Brownstein Catherine C Costigan Michael M Ebrahimi-Fakhari Darius D Lai Abbe A O'Donnell-Luria Anne A Paciorkowski Alex R AR Pinto Anna A Pugh John J Rodan Lance L Roe Eugene E Swanson Lindsay L Zhang Bo B Kruer Michael C MC Sahin Mustafa M Poduri Annapurna A Srivastava Siddharth S

Annals of clinical and translational neurology 20220124 2

<h4>Objectives</h4>Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP.<h4>Methods</h4>We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one ri ...[more]

PMID: 35076175

Similar Datasets

Project description:ImportanceCerebral 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.ObjectiveTo 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.ExposuresExome sequencing with copy number variant detection.Main outcomes and measuresThe primary outcome was the molecular diagnostic yield of exome sequencing.ResultsAmong 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 relevanceAmong 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.

Dataset Information

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

Objectives

Methods

Results

Interpretation

Publications

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

Similar Datasets

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