Objective Epilepsy‐associated developmental lesions, including malformations of cortical development and low‐grade developmental tumors, represent a major cause of drug‐resistant seizures requiring surgical intervention in children. Brain‐restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. Methods We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high‐depth targeted DNA sequencing. Results We uncovered candidate disease‐causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen‐activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B‐raf proto‐oncogene, serine/threonine kinase [BRAF], and KRAS proto‐oncogene, GTPase [KRAS]) was associated with low‐grade epilepsy‐associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one‐half of epilepsy‐associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease‐causing variants in genes not yet associated with focal cortical dysplasia. Significance These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.
Many daily activities require a basic understanding of math. Numeracy, which refers to individual differences in the ability to understand numerical concepts and work with probabilities, has been linked to health-related decision-making and medical and financial outcomes. Whether affective influences impact numeracy has not been experimentally assessed, although research has shown that emotions impact judgments and decisionmaking. Stress is one commonly experienced affective influence that could impact numeracy. We examined whether objective and subjective numeracy were influenced by stress induced from anticipating giving a speech in a laboratory setting. We also examined the association of self-reported math anxiety, or apprehension pertaining to mathematics, with objective and subjective numeracy. Two experiments were conducted; the second was a direct replication. Undergraduate students (Experiment 1, n ϭ 99; Experiment 2, n ϭ 139) were randomly assigned to one of two conditions: a stress induction or a neutral condition. Whereas neither objective nor subjective numeracy significantly differed across conditions, math anxiety was a consistent predictor of objective and subjective numeracy. Math anxiety and baseline perceived stress did not consistently moderate any effects. These findings have implications for health care, educational, and financial contexts in which people must make decisions that involve complex numbers. Public Significance StatementPeople's ability to work with and interpret numbers correctly, or their numeracy, influences medical and financial decision-making and outcomes. In the present study, people with more math anxietythat is, apprehension about math-performed worse on a numeracy measure and rated their numeracy as worse. Some participants were placed under stress, yet their numeracy was not impacted relative to participants who did not experience stress. This suggests that it may be worthwhile to test whether interventions that reduce math anxiety can improve health decision-making.
Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. We enrolled 50 children undergoing epilepsy surgery into a translational research study. We performed exome and RNA-sequencing of resected brain tissue samples to identify somatic variation. We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). We confirmed somatic findings using high-depth targeted DNA sequencing. In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. Somatic structural variation accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes (EEF2, NAV2, PTPN11) not yet associated with focal cortical dysplasia. These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.
Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the
There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 months of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder-Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. While Sanger sequencing confirmed the de novo status in our proband, PCR and deep targeted resequencing to ~84,000-175,000x depth revealed that the variant is present in blood from the unaffected mother at ~3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.
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