Genomic analysis identifies masqueraders of full‐term cerebral palsy

Abstract

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.

Recurrent de novo MAPK8IP3 variants cause neurological phenotypes

“…Exome sequencing was performed as previously reported in three institutions: Tohoku University, the National Center for Child Health and Development, and Yokohama City University.…”

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

“…It was recognized in 2016 that some GNAO1 mutations result in movement disorders without epilepsy (Kulkarni et al, 2016;Saitsu et al, 2016). To date there are over 70 published cases of children with mutations in GNAO1 presenting with early infantile epileptic encephalopathy (EIEE17: OMIM 615473) and/or neurodevelopmental disorder with involuntary movements (NEDIM: OMIM 617493) (Nakamura et al, 2013;Consortium et al, 2014;Law et al, 2015;Talvik et al, 2015;Ananth et al, 2016;Consortium, 2016;Dhamija et al, 2016;Gawlinski et al, 2016;Kulkarni et al, 2016;Marcé-Grau et al, 2016;Menke et al, 2016;Saitsu et al, 2016;Sanem et al, 2016;Arya et al, 2017;Danti et al, 2017;Sakamoto et al, 2017;Schorling et al, 2017;Blumkin et al, 2018;Bruun, 2018;Gerald et al, 2018;Honey et al, 2018;Koy et al, 2018;Marecos et al, 2018;Okumura et al, 2018;Rim et al, 2018;Schirinzi et al, 2018;Takezawa et al, 2018;Waak et al, 2018;Xiong et al, 2018;Meredith et al, 2019). This article has not been copyedited and formatted.…”

Construction and Integration of Three De Novo Japanese Human Genome Assemblies toward a Population-Specific Reference

“…To evaluate whether JG1 is a suitable reference genome for clinical NGS analyses, we examined exomes of Japanese families with rare diseases 38 . The sample cohort consisted of 22 individuals from six trio families and one quartet family.…”