Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy

Abstract

SummaryObjectiveEpileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic‐based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high‐throughput next‐generation sequencing (NGS) was used to investigate the genetic causes of non‐syndromic cryptogenic neonatal/infantile EE (NIEE).MethodsWe have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work‐up, were negative. Using NGS, we distinguished a panel of 430 epilepsy‐associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as “pathogenic,” “likely pathogenic” and “uncertain significance,” according to the American College of Medical Genetics (ACMG) guidelines.ResultsPathogenic or likely pathogenic variants were identified in six genes (ALG13 [1], CDKL5 [2], KCNQ2 [2], PNPO [1], SCN8A [1], SLC9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in DNM1 and TUBA8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases.SignificanceThe diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early‐onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM1 and TUBA8.

Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency

“…Moreover, microcephaly was described in five cases 15‐18 . Autistic spectrum disorders and attention‐deficit/hyperactivity disorder (ADHD) were observed in three patients 7,13,19 …”

“…[15][16][17][18] Autistic spectrum disorders and attention-deficit/hyperactivity disorder (ADHD) were observed in three patients. 7,13,19 3.1. and 14% (n = 5) responded only after several days with gradual seizure control. We noted that all of the responsive patients became PLP-dependent and dose adjustment was needed to manage sick days.…”

Confirming the pathogenicity of NECAP1 in early onset epileptic encephalopathy

“…Of interest, DNM1, which is another gene involved in the CME pathway, has been reported to cause epileptic encephalopathy by multiple cohort studies. 4,[9][10][11][12][13][14][15][16][17][18] DNM1 gene encodes for dynamin-1 protein, which is essential for the scission of newly formed CME vesicles. 19 Patients with DNM1 mutation have severe ID and early onset intractable seizures ( Table 1).…”

Defining the phenotype of FHF1 developmental and epileptic encephalopathy

“…With the application of next-generation sequencing approaches, the number of known monogenic determinants underlying DEEs has grown rapidly. To date, a genetic etiology can be identified in upward of 30% of case (60-80% for epilepsies with neonatal onset) [3,4] and it consists mainly of de novo variants in genes encoding neuronal ion channels or proteins involved in synaptic transmission, regulatory, and developmental functions [5,6].…”