Genetic Diagnosis in Children with Epilepsy and Developmental Disorders by Targeted Gene Panel Analysis in a Developing Country

Abstract

Background and Purpose: In childhood epilepsy, genetic etiology is increasingly recognized in recent years with the advent of next generation sequencing. This has broadened the scope of precision medicine in intractable epilepsy, particularly epileptic encephalopathy (EE). Developmental disorder (DD) is an integral part of childhood uncontrolled epilepsy. This study was performed to investigate the genetic etiology of childhood epilepsy and DD.Methods: In this study, 40 children with epilepsy and DD with positive genetic mutation were included retrospectively. It was done in a tertiary care referral hospital of Bangladesh from January 2019 to December 2020. Genetic study was done by next generation sequencing. In all cases electroencephalography, neuroimaging was done and reviewed.Results: In total, 40 children were enrolled and the average age was 41.4±35.850 months with a male predominance (67.5%). Generalized seizure was the predominant type of seizure. Regarding the association, intellectual disability and attention deficit hyperactivity disorder was common. Seventeen cases had genetically identified early infantile EE and common mutations observed were SCN1A (3), SCN8A (2), SLC1A2 (2), KCNT1 (2), and etc. Five patients of progressive myoclonic epilepsy were diagnosed and the mutations identified were in KCTD7, MFSD8, and CLN6 genes. Three cases had mitochondrial gene mutation (MT-ND5, MT-CYB). Some rare syndromes like Gibbs syndrome, Kohlschütter-Tönz syndrome, Cockayne syndrome, Pitt-Hopkins syndrome and cerebral creatine deficiency were diagnosed.Conclusions: This is the first study from Bangladesh on genetics of epilepsy and DD. This will help to improve the understanding of genetics epilepsy of this region as well as contribute in administering precision medicine in these patients.

Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases

“…CSNK2A1 and CSNK2B variants were compiled from the OCNDS literature ( Iossifov et al, 2014 ; Okur et al, 2016 ; Trinh et al, 2017 ; Yuen et al, 2017 ; Akahira-Azuma et al, 2018 ; Chiu et al, 2018 ; Owen et al, 2018 ; Duan et al, 2019 ; Nakashima et al, 2019 ; Martinez-Monseny et al, 2020 ; van der Werf et al, 2020 ; Wang et al, 2020 ; Wu R et al, 2020 ; Xu et al, 2020 ; Dominguez et al, 2021 ; Wu et al, 2021 ), and the POBINDS literature ( Poirier et al, 2017 ; Sakaguchi et al, 2017 ; Fernández-Marmiesse et al, 2019 ; Li et al, 2019 ; Nakashima et al, 2019 ; Ernst et al, 2021 ; Rahman and Fatema 2021 ; Selvam et al, 2021 ; Valentino et al, 2021 ; Yang et al, 2021 ). We also compiled CSNK2A1 and CSNK2B variants from the DECIPHER database v11.6 ( https://www.deciphergenomics.org ; last accessed 1/5/22) ( Firth et al, 2009 ), Simons Searchlight Single Gene Dataset v8.0, AutDB Autism Informatics Portal ( http://autism.mindspec.org/autDB/ ; last accessed 1/5/22) ( Basu et al, 2009 ), and website/url to ClinVar, “( https://www.ncbi.nlm.nih.gov/clinvar/ ) (last accessed 1/5/22) ( Landrum et al, 2018 ).…”

“…Common clinical features of patients with OCNDS include intellectual disability, developmental delay, autism spectrum disorder (ASD), language impairment, ataxia, attention deficit hyperactivity disorder, microcephaly and craniofacial dysmorphisms ( Iossifov et al, 2014 ; Okur et al, 2016 ; Trinh et al, 2017 ; Yuen et al, 2017 ; Akahira-Azuma et al, 2018 ; Chiu et al, 2018 ; Owen et al, 2018 ; Duan et al, 2019 ; Nakashima et al, 2019 ; Martinez-Monseny et al, 2020 ; van der Werf et al, 2020 ; Wang et al, 2020 ; Wu R et al, 2020 ; Xu et al, 2020 ; Dominguez et al, 2021 ; Wu et al, 2021 ). Typical clinical features of patients with POBINDS include early onset seizures, intellectual disability and developmental delay, although some patients are also characterized by ASD, attention deficit hyperactivity disorder, language impairment and facial dysmorphisms ( Poirier et al, 2017 ; Sakaguchi et al, 2017 ; Fernández-Marmiesse et al, 2019 ; Li et al, 2019 ; Nakashima et al, 2019 ; Ernst et al, 2021 ; Rahman and Fatema 2021 ; Selvam et al, 2021 ; Valentino et al, 2021 ; Yang et al, 2021 ).…”

“…Most published gene variants are missense, and the rest are nonsense, splice and frameshift variants. Forty CSNK2B variants ( de novo ) are published in both male and female individuals with POBINDS ( Poirier et al, 2017 ; Sakaguchi et al, 2017 ; Fernández-Marmiesse et al, 2019 ; Li et al, 2019 ; Nakashima et al, 2019 ; Ernst et al, 2021 ; Rahman and Fatema 2021 ; Selvam et al, 2021 ; Valentino et al, 2021 ; Yang et al, 2021 ). A small subset of the identified CSNK2B variants are missense, and the rest are nonsense, splice and frameshift variants.…”

Clinical Characteristics and Etiology of Epilepsy in Children Aged Below Two Years: Perspective From a Tertiary Childcare Hospital in South Punjab, Pakistan

“…Moreover, other researchers in the past have pointed around 13% of cases of epilepsy have genetic etiology [16,20]. Recent decades have seen significant advancements regarding the identification of the genetic etiology of epilepsy [21].…”

Kctd7 deficiency induces myoclonic seizures associated with Purkinje cell death and microvascular defects

“…Mutations in the potassium channel tetramerization domain-containing (KCTD) 7 ( KCTD7 ) gene cause progressive myoclonic epilepsy (PME) 3 ( ), a rare but often crippling neurodevelopmental and epileptic disorder. KCTD7 -related progressive myoclonic epilepsy ( KCTD7 -PME) has been reported in over 55 patients with more than 40 unique variants ( Burke et al, 2021 ; Dai et al, 2019 ; Dudipala et al, 2021 ; Farhan et al, 2014 ; Kousi et al, 2012 ; Kozina et al, 2020 ; Lindy et al, 2018 ; Mastrangelo et al, 2019 ; Mei et al, 2019 ; Metz et al, 2018 ; Rahman and Fatema, 2021 ; Vairo et al, 2017 ; Van Bogaert et al, 2007 ; Blumkin et al, 2012 ; Moen et al, 2016 ). Affected patients carry homozygous or compound heterozygous mutations, whereas heterozygous family members are neurologically unaffected ( Metz et al, 2018 ).…”