Clinically relevant copy number variations detected in cerebral palsy

Oskoui, Maryam; Gazzellone, Matthew J.; Thiruvahindrapuram, Bhooma; Zarrei, Mehdi; Andersen, John; Wei, John; Wang, Zhuozhi; Wintle, Richard F.; Marshall, Christian R.; Cohn, Ronald D.; Weksberg, Rosanna; Stavropoulos, Dimitri J.; Fehlings, Darcy; Shevell, Michael; Scherer, Stephen W.

doi:10.1038/ncomms8949

Cited by 128 publications

(118 citation statements)

References 60 publications

Supporting

Mentioning

112

Contrasting

Unclassified

Order By: Relevance

“…No significant pathogenic CNVs were identified with aCGH in this study, unlike other previous reports,3, 36 in which pathogenic CNVs were identified in 9.6–31% of patients with aCGH. This wide range of proportions could be explained by variations in case selection or differences in the criteria used to evaluate pathogenicity.…”

Section: Discussioncontrasting

confidence: 96%

See 1 more Smart Citation

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveCerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full‐term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders.MethodsA total of 107 patients—all full‐term births—without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole‐exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines.ResultsPathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1,CYP2U1,SPAST,GNAO1,CACNA1A,AMPD2,STXBP1, and SCN2A. Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice‐site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments.InterpretationThe high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full‐term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

show abstract

Section: Discussioncontrasting

confidence: 96%

“…Both genetic and environmental factors contribute to the etiology of CP. Recent studies have suggested that a larger number of rare pathogenic genetic variants2 or pathogenic copy number variations (CNVs)3 contribute to CP than previously expected 4. This suggests that “masquerading” genetic diseases can be misdiagnosed as CP 5.…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Therefore, the candidate gene or variant has not yet been identified (3). Secondly, it has been shown that MA can enlight account for 10-20% of CPs (3,4). Chromosomal MA is a new, high-resolution chromosome analysis technique.…”

mentioning

confidence: 99%

“…Beneath neonatal asphyxia, there may be neuromuscular diseases such as Prader-Willi syndrome, congenital myotonic dystrophy, and many clinical conditions leading to hypotonia (1). Possible genetic factors should be investigated in patients with a history of premature birth or hypoxia who present with motor problems prior to the diagnosis of CP (1,4).…”

mentioning

confidence: 99%

“…In motor-mental retardation and autism spectrum disorders with or without congenital anomalies, MA is the first test to be performed together with classic karyotype analysis. It should be used in selected cases in neurologic phenotypes such as CP and epilepsy (2,4). Third, NGS methods can be used to diagnose rare and unknown genetic diseases by genome-wide sequencing (5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cerebral Palsy and Genetics

Akçakaya¹,

Yapıcı²,

Özbek³

2018

tnd

View full text Add to dashboard Cite

Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Moreno-De-Luca

Millan²,

Pesacreta

et al. 2021

JAMA

View full text Add to dashboard Cite

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.

show abstract

Clinically relevant copy number variations detected in cerebral palsy

Cited by 128 publications

References 60 publications

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Cerebral Palsy and Genetics

Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy

Contact Info

Product

Resources

About