Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome

Abstract

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…This variant was not highlighted in the original report, because mosaic variants at this level in leukocytes had been excluded, but it has since been confirmed to be mosaic and absent in parents (unpublished data). This patient exhibited infantile spasms at age 4 months, developmental delay, and normal MRI, similar to other reported cases with germline SLC35A2 variants . In contrast to the 2 cases with mosaic SLC35A2 variants in brain tissue who presented with epileptic encephalopathy and abnormal MRI, the NLFE cases with mosaic SLC35A2 variants in brain tissue did not present with epileptic encephalopathy or infantile seizure onset.…”

“…Subsequently, germline heterozygous putative loss-of-function de novo variants, including missense, nonsense, and frameshift indels, in SLC35A2 have been identified in multiple girls with epileptic encephalopathy (see Fig 4). 14,46,47,49 The lack of males with germline variants in this gene likewise supports the assertion that an intact allele, in at least some tissues of the body, is required for survival. Across all previously and our newly reported associated phenotypes, there are both protein-truncating and missense variants observed, suggesting that the missense variants are likely acting through a loss-of-function mechanism (see Fig 4).…”

Whole‐exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome

“…Transferrin isoelectric focusing showed increased asialo-and disialotransferrin fractions. Two other missense mutations were found in four brothers affected with intellectual disability and in a male patient with ISs and optic nerve atrophy (15,16). 10A1280 was the only patient with the p.Asn107Ser in whom transferrin glycosylation was assayed.…”

Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion

“…Trio sequencing is a powerful method for determining causal variants in unexplained sporadic epileptic encephalopathy, although it is usually applied on a research basis . In two recent studies specifically investigating unexplained infantile spasms, 35‐ and 63‐gene panels did not identify any causal variants when compared to trio sequencing, which identified causal variants in 28% and 36%, respectively . Further candidate genes are often identified using trio sequencing .…”

“…In two recent studies specifically investigating unexplained infantile spasms, 35‐ and 63‐gene panels did not identify any causal variants when compared to trio sequencing, which identified causal variants in 28% and 36%, respectively . Further candidate genes are often identified using trio sequencing . However, NGS technology and its applications are rapidly changing.…”