Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Andrés Moreno-De-Luca, MD^1,2,3,4; Francisca Millan, MD⁵; Denis R. Pesacreta, BS¹; et alHouda Z. Elloumi, PhD⁵; Matthew T. Oetjens, PhD¹; Claire Teigen, MS⁵; Karen E. Wain, MS^1,2; Julie Scuffins, MS⁵; Scott M. Myers, MD¹; Rebecca I. Torene, PhD⁵; Vladimir G. Gainullin, PhD⁵; Kevin Arvai, MS⁵; H. Lester Kirchner, PhD⁶; David H. Ledbetter, PhD^1,2; Kyle Retterer, MS⁵; Christa L. Martin, PhD^1,2

JAMA. 2021;325(5):467-475. doi:10.1001/jama.2020.26148

Question  What is the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) among patients with cerebral palsy?

Findings  In this cross-sectional study that included 2 independent cohorts of 1526 patients with cerebral palsy, the molecular diagnostic yield of exome sequencing was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients.

Meaning  This study identified pathogenic and likely pathogenic variants among some patients with cerebral palsy, although further research is needed to understand the clinical implications of these findings.

Abstract

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.

Source: http://pctu.edu.vn/vn/new-issue-mobile-stroke-units-and-stroke-outcomes-yield-of-exome-sequencing-for-cerebral-palsy-uspstf-guideline-on-screening-for-carotid-artery-stenosis-and-more.html