Unexplained Early Infantile Epileptic Encephalopathy in Han Chinese Children: Next-Generation Sequencing and Phenotype Enriching

Arafat, Ahmed; Peng, Jing; Ma, Yue; Miao, Pu; Gai, Nan; He, Fang; Chen, Chen; Yin, Fei

doi:10.1038/srep46227

Cited by 30 publications

(31 citation statements)

References 53 publications

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“…Ala1650Val variant has not been described before (#26), but has been seen several times with a threonine (Ala1650Thr) substitution in patients with severe DEE. 5,7,35 Arg1872Gln has also been seen several times in patients with severe DEE 7,36 ; however, we found it in a sib pair, with normal intellect and focal epilepsy (#34). The Gly1483Lys variant has previously been described in BFIS 17 ; the patient in this study (#18) carrying this variant has a very mild phenotype, with only speech delay, sporadic seizures, and discrete focal EEG abnormalities.…”

Section: Discussioncontrasting

confidence: 54%

The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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Summary Objective Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A‐related epilepsies. Methods A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results We found 36 probands who presented with an SCN8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance With this study, we explore the electroclinical features of an intermediate SCN8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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Section: Discussioncontrasting

confidence: 54%

The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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“…His presentation is more in keeping with an early onset (defined as less than 3 months) developmental and epileptic encephalopathy, as he did not have the burst‐suppression EEG signature of Ohtahara syndrome. All reported cases of pathogenic variants in ARX that lead to phenotypes of seizure onset prior to 3 months are captured in Table (Arafat et al, ; Bettella et al, ; Conti et al, ; Eksioglu et al, ; Fullston et al, ; Fullston et al, ; Giordano et al, ; Kato et al, ; Kwong et al, ; Sartori et al, ; Stromme et al, ; Tapie et al, ). Interestingly, several insertion variants in exon 5 of ARX that are predicted to cause altered or early termination of the ARX protein lead to severe and early onset epilepsy syndromes rather than the brain malformation/XLAG outcomes associated with complete loss‐of‐function variants (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenic variants within the homeodomain region are well characterized and generally abolish binding of ARX to target DNA sequences (Shoubridge, Tan, Seiboth, & Gecz, ). There are several variants, including insertion variants in exon 5 of ARX that are predicted to cause frameshift variants that are pathogenic, resulting in altered or early termination of the ARX protein, but not complete loss of function (Arafat et al, ; Bettella et al, ; Conti et al, ; Eksioglu, Pong, & Takeoka, ; Fullston et al, ; Fullston et al, ; Giordano et al, ; Kato, Koyama, Ohta, Miura, & Hayasaka, ; Kwong, Ho, Fung, & Wong, ; Sartori et al, ; Stromme et al, ; Tapie et al, ). These cases invariably lead to infantile onset developmental and epileptic encephalopathies such as Ohtahara Syndrome (also called early infantile epileptic encephalopathy) and West syndrome.…”

Section: Introductionmentioning

confidence: 99%

Splice variant in ARX leading to loss of C‐terminal region in a boy with intellectual disability and infantile onset developmental and epileptic encephalopathy

Shoubridge

Jackson

Grinton

et al. 2019

American J of Med Genetics Pt A

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Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected individuals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively.Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband. K E Y W O R D S ARX, epilepsy, intellectual disability, Ohtahara syndrome, splice 1 | INTRODUCTION Aristaless-related homeobox (ARX) gene [NM_139058.2] is frequently mutated to cause X-linked intellectual disability with or without comorbidities including autism spectrum disorder, epilepsy, lissencephaly, and ambiguous genitalia. ARX belongs to the paired-type homeobox transcription factor family, which is characterized by the presence of a conserved 60 amino acid DNA-binding domain called the homeodomain. Other important domains present in ARX include an octapeptide domain, four polyalanine tracts, three nuclear localization signals and an Aristaless domain at the C-terminal end of the protein. There are more than 60 different pathogenic variants reported across ARX which give rise to a broad range of phenotypes, with the most common pathogenic variants being expansions of the first and second polyalanine tracts (c.304ins (GCG)7 and c.429_452dup) (reviewed in [Shoubridge, Fullston, & Gecz, 2010]).

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“…The study included 72 Chinese WS patients with no family history and with negative findings in the following: (i) metabolic, structural, immunological, and infectious etiologies (International League Against Epilepsy recommendations); (ii) chromosomal disorders (ie, Down's syndrome), copy number variation (CNV) diseases, and monogenic disorders (ie, Angelman syndrome or tuberous sclerosis complex); and (iii) Genetic‐structural modification of the brain (ie, tuberous sclerosis or DCX mutations leading to lissencephaly) . Peripheral blood samples were collected from patients and their parents via venipuncture …”

Section: Methodsmentioning

confidence: 99%