Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: A single centre experience

Abstract

Introduction:A paucity of literature exists on genotype-phenotype correlates of 'unknown-etiology' infantile-onset developmental-epileptic encephalopathies (DEE) from India. The primary objective was to explore the yield of genetic testing in identifying potential disease causing variants in electro-clinical phenotypes of DEE Methods:An observational hospital-based study was undertaken on children with unexplained refractory seizure-onset ≤12 months age and developmental delay, whose families consented and underwent genetic testing during a three year time period (2016)(2017)(2018) by next-generation sequencing (NGS) or multiplex ligand protein amplification. Yield was considered based on demonstration of pathogenic/likely pathogenic variants only and variants of unknown significance (VUS) were documented. Results:Pathogenic/likely pathogenic variants were identified in 26 (31.7%) out of 82 children with DEE. These included those variants responsible for primarily DEE-21(76.7%); neuro-metabolic disorders-3(18.6%) and chromosomal deletions-2(4.7%). Of these patients, early-infantile epilepsy onset ≤ 6months age was noted in 22(84.6%). The DEE studied included Ohtahara syndrome associated with STXBP1 and SCN8A variants with yield of 50% (2/4 tested); early myoclonic encephalopathy (no yield in 2); West syndrome with CDKL5, yield of 13.3% (2/15 tested); epilepsy of infancy with migrating partial seizures due to CACNA1A and KCNT1 variants, yield of 67% (2/3 tested); DEE-unclassified with KCNQ2, AP3B2, ZEB2, metabolic variants (SUOX, ALDH7A1, GLDC) and chromosome deletions (chr 1p36, chr2q24.3); yield of 32% (8/25 tested). Patients with Dravet syndrome/Dravet-like phenotypes (N=33) had variants in SCN1A (N=10), SCN1B, CHD2; yield of 36.4% (12/33 tested; 57.1% from NGS). Eighteen patients with potential variants (SCN1A, SCN2A, SCN8A, KCNQ2, ALDH7A1 which also included VUS) could be offered targeted therapy. Conclusions:Our study confirms a good yield of genetic testing in neonatal and infantile-onset DEE provided robust phenotyping of infants is attempted with prognostic and therapeutic implications, particularly relevant to centres with resource constraints.

Landscape of genetic infantile epileptic spasms syndrome—A multicenter cohort of 124 children from India

“…This might be because seven children with PDE (three unrelated cases had the same variant; possible founder variation) were contributed by a single center catering to a population with a high prevalence of consanguinity. The frequencies of the other monogenic disorders, such as SCN2A, CDKL5, STXBP1, WWOX , etc., were comparable to that reported in previous cohorts 8,10,12–15 . The other common genes reported in previous cohorts, such as ARX, TSC, TUBA1A , Miller Dieker syndrome, and other structural neurometabolic disorders at initial presentation, were not observed in the current study since these were systematically excluded at the outset due to the associated characteristic neuroimaging abnormalities 8,10,12–14 .…”

“…Many genetic abnormalities were associated with the late onset of ES (beyond 1 year of age). Some genes like ALDH7A1, CDKL5, KCNQ2, KCNT1, NTRK2, STXBP1, UGP2 , and WWOX characteristically had an early infantile‐onset in the current cohort similar to that described previously, while genetic variations in NRROS and SYNGAP1 (2/3) had onset of ES beyond 1 year of life like that reported in most patients with these disorders 10,12–15,21,27 …”

“…Overall, single‐gene disorders were the most common genetic category, complementing the idea behind whole exome sequencing as the first‐line genetic investigation for these children 5,9,36 . The commonest monogenic disorder observed was PDE, contrasting the findings of large genetic IESS cohorts 8,10,12–15 . This might be because seven children with PDE (three unrelated cases had the same variant; possible founder variation) were contributed by a single center catering to a population with a high prevalence of consanguinity.…”

“…It is well understood now that within the genetic subgroup, implicated genes are widely heterogeneous. 5,[8][9][10][11][12][13][14][15][16][17] However, the literature on the novel genetic variations underlying IESS is mostly available from the developed Western countries through funded multinational consortia, such as the Epi4K consortium, 8 which is skewed toward these countries and does not represent the global genetic landscape of IESS.…”

Novel homozygous GLDC variant causing late-onset glycine encephalopathy: A case report and updated review of the literature

“…Brain MRI often shows thin and shortened corpus callosum, hydrocephalus, cerebral atrophy, ventricular dilatation, hypomyelination [ 1 ]. Most of patients with glycine encephalopathy have an uneventful pregnancy with normal delivery ( Supplementary Table S1 ) [ [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] ]. Here, we document an 8-year-old-boy with late-onset nonketotic hyperglycinemia (NKH) in whom WES revealed a novel homozygous GLDC likely pathogenic variant c.707G > A p.(Arg236Gln).…”