Copy number variations in cryptogenic cerebral palsy

Segel, Reeval; Ben‐Pazi, Hilla; Zeligson, Sharon; Fatal-Valevski, Aviva; Aran, Adi; Gross‐Tsur, Varda; Schneebaum-Sender, Nira; Shmueli, Dorit; Lev, Dorit; Perlberg, Shira; Blumkin, Luba; Deutsch, Lisa; Levy-Lahad, Ephrat

doi:10.1212/wnl.0000000000001494

Cited by 90 publications

(71 citation statements)

References 29 publications

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“…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: 95%

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

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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.

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Section: Discussioncontrasting

confidence: 95%

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

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“…Such inheritance pattern is not unusual for other neurodevelopmental disorders like intellectual disability or autism. In a new study from Israel 16 cerebral palsy cases out of 52 cases (31%) of unknown etiology had CNVs that were likely to be pathogenic and 12 of these were de novo 57 Conclusion. The long-held belief that most or many cases of cerebral palsy are due to trauma or asphyxia around the time of birth and that earlier intervention can prevent the neuropathology is not evidence based, has held back research into other pathways and has fuelled unwarranted litigation that has had an untoward effect on modern maternity care and maternal outcomes.…”

Section: Accepted Manuscriptmentioning

confidence: 88%

Cerebral palsy: causes, pathways, and the role of genetic variants

MacLennan

Thompson

Gécz

2015

American Journal of Obstetrics and Gynecology

358

288

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Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.

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“…[20][21][22] CNV analysis may be diagnostically and prognostically valuable in clinical settings, and CNV studies of CP cohorts have already been instructive by implicating genes relevant to CP neurobiology within the genomic interval that has been duplicated or deleted. [20][21][22] CNV analysis may be diagnostically and prognostically valuable in clinical settings, and CNV studies of CP cohorts have already been instructive by implicating genes relevant to CP neurobiology within the genomic interval that has been duplicated or deleted.…”

mentioning

confidence: 99%

The genetic basis of cerebral palsy

Fahey

MacLennan

Kretzschmar

et al. 2017

Develop Med Child Neuro

155

123

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Although prematurity and hypoxic-ischaemic injury are well-recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one-third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention.

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Copy number variations in cryptogenic cerebral palsy

Abstract: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology.

Cited by 90 publications

References 29 publications

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Cerebral palsy: causes, pathways, and the role of genetic variants

The genetic basis of cerebral palsy

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