<i>De novo</i>point mutations in patients diagnosed with ataxic cerebral palsy

Schnekenberg, Ricardo Parolin; Perkins, Emma M.; Miller, Jack W.; Davies, Wayne I. L.; D’Adamo, Maria Cristina; Pessia, Mauro; Fawcett, Katherine A.; Sims, David; Gillard, Elodie; Hudspith, Karl A. Z.; Skehel, Paul; Williams, Jonathan; O’Regan, Mary; Jayawant, Sandeep; Jefferson, R J; Hughes, Sarah M.; Lustenberger, A; Ragoussis, Jiannis; Jackson, Mandy; Tucker, Stephen J.; Németh, Andrea H.

doi:10.1093/brain/awv117

Cited by 134 publications

(132 citation statements)

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“…Among the causative variants identified in the nine patients, the variants in SPAST , GNAO1 , CACNA1A, and STXBP1 have been previously reported,27, 28, 29, 30, 31, 32 whereas the variants in the other genes ( CTNNB1 , CYP2U1 , AMPD2 , and SCN2A ) were novel. Of all the identified candidate genes, only SPAST , STXBP1 , and SPTBN2 have been previously reported in CP patients 33, 34, 35. In five cases, we identified eight unknown significant candidate variants of five genes ( UBA1 , AMER1 , FAT4 , GPR98 , and SPTBN2 ).…”

Section: Resultsmentioning

confidence: 86%

“…Furthermore, case 17 was also a compound heterozygote of SPTBN2 variants. SPTBN2 has been identified in both autosomal dominant and autosomal recessive spinocerebellar ataxia,42 together with CP 34. Although both SPTBN2 variants in case 17 were classified as having uncertain significance and the patient's clinical presentation was consistent with SCN2A ‐related disorder, we cannot eliminate the possibility that those variants in SPTNBN2 could contribute to the patient's phenotype.…”

Section: Discussionmentioning

confidence: 90%

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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: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 90%

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

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“…In order not to exclude variants of potential pathological significance, in the regulatory regions, promoters, UTRs, intron-exon splice sites should also be analyzed. Further filtering to identify causal mutations depends upon the mode of inheritance; for example, with a recessive disorder, one would necessarily focus on homozygous and compound heterozygous SNVs [13,14,15]. Single-nucleotide polymorphism (SNP) information embedded within the exome sequencing data has also been used for homozygosity mapping or analysis; this is important in order to narrow down regions harbouring the mutations underlying recessive disorders [16].…”

Section: Discovering Germline Variants For Rare Mendelian Disordersmentioning

confidence: 99%

The Rise and Rise of Exome Sequencing

Cooper

Patrinos

2016

Public Health Genomics

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Beginning in 2009, the advent of exome sequencing has contributed significantly towards new discoveries of heritable germline mutations and de novo mutations for rare Mendelian disorders with hitherto unknown genetic aetiologies. Exome sequencing is an efficient tool to identify disease mutations without the need of a multi-generational pedigree. Sequencing a single proband or multiple affected individuals has been shown to be successful in identifying disease mutations, but parents would be required in the case of de novo mutations. In addition to heritable germline and de novo mutations, exome sequencing has also succeeded in unravelling somatic driver mutations for a wide range of cancers through individual studies or international collaborative effort such as the Cancer Genome International Consortium. By contrast, the application of exome sequencing in complex diseases is relatively limited; probably it would be too expensive were it applied to thousands of samples to achieve the statistical power for rare or low frequency variants (<1%). On top of research discoveries, the application of exome sequencing as a diagnostic tool is also increasingly evident. In this article, we summarize and discuss the progress that has been made in these areas during almost a decade.

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“…It matters little that medicine today has almost no real knowledge concerning the length of time and degree of hypoxemia required to produce CP or any other neurologic injury in a previously healthy fetus [56,[59][60][61]. It does not matter either that fifty years of CP-EFM research has repeatedly proven asphyxia to be a cause of only a tiny fraction of CP cases, while the same research identified a multiplicity of antenatal-post-natal causative factors, a number of which are silent and impossible to recognize until years later [1-11, 21, 39, 56, 59-63] in addition to the most recent genetic studies revealing the large number of plausible mutations, de novo and inherited, contributing to cerebral palsy causation [10,64,65]. The public, trial lawyers, and a surprising number of physicians, including obstetricians, still believe the oxygen-deprivation-is-the-sole-cause-of-perinatalbrain-damage and CP myth [47][48][49][66][67][68][69][70][71].…”

Section: Journal Of Childhood and Developmental Disorders Issn 2472-1786mentioning

confidence: 99%