RESUMEN
INTRODUCTION: Biallelic variants in thiamine pyrophosphokinase 1 (TPK1) are known to cause thiamine metabolism dysfunction syndrome 5 (THMD5). This disorder is characterized by neuroregression, ataxia and dystonia with basal ganglia abnormalities on neuroimaging. To date, 27 families have been reported with THMD5 due to variants in TPK1. METHODS: We ascertained three individuals from three unrelated families. Singleton exome sequencing was performed on all three individuals, followed by in silico mutagenesis of the mutant TPK protein. Additionally, we reviewed the genotypic and phenotypic information of 27 previously reported individuals with THMD5. RESULTS: Singleton exome sequencing revealed a novel homozygous variant c.620A>T p.(Asp207Val) in TPK1 (NM_022445.4) in all three individuals. In silico mutagenesis of the mutant protein revealed a decrease in protein stability and altered interactions with its neighboring residues compared to the wild-type protein. Thus, based on strikingly similar clinical and radiological findings compared to the previously reported individuals and with the support of in silico mutagenesis findings, the above-mentioned variant appears to be the probable cause for the condition observed in the affected individuals in this study. CONCLUSION: We report a novel homozygous variant in TPK1, which appears to be recurrent among the Indian population.
RESUMEN
Background: Consumer behavior research and neurology are combined in the emerging discipline of neuromarketing. Neuromarketing is considered to be one of emerging field to study how consumer's brain reacts to advertisement and other brand's message by observing brainwave, eye, and skin response. The current study examined the emerging field of constructs of neuromarketing like social, attention, technology, and emotions to examine Indian consumer's buying behavior. Purpose: To study the validity and reliability of constructs of neuromarketing that examines consumer's buying behavior among Indian consumers. Methods: A sample of 191 people of different age groups was considered in the study. A random sampling technique was used for data collection. The self-designed questionnaire used for the measurement of neuromarketing constructs and consumers' buying behavior. The current study applied SPSS and AMOS software to validate the measurement model of neuromarketing. Results: The Kaiser-Meyer-Olkin (KMO) and Bartlett's Test's value is 0.784 and this value confirmed that the sample is adequate for factor analysis. Apart from that, the five constructs of neuromarketing - Attention (A), Social (SC), Technological (T), Emotion (E), and Consumer Buying Behavior (BB) had shown the value of Cronbach's alpha to be more than 0.7. Confirmatory Factor Analysis (CFA) had shown value of average variance explained of each constructs 0.5 and composite reliability more than 0.7 which indicates excellent construct validity of constructs for model formation of neuromarketing. The study also validates measurement research model of neuromarketing on the basis of model fit index (chi-square/df = 3.397, RMSEA = 0.10, GFI = 0.92, and CFI = 0.87). Conclusion: The present study had shown good validity and reliability of constructs of neuromarketing and also proved that marketers can apply these constructs to examine behavior pattern of consumers.
RESUMEN
Biallelic variants in RSPRY1 have been found to result in spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. The phenotype in our patients resembles spondyloepimetaphyseal dysplasia, Faden-Alkuraya type. Thus, our study provides further evidence to support the association of RSPRY1 variants with spondyloepimetaphyseal dysplasia. We observed joint dislocation as a novel clinical feature of this condition.
Asunto(s)
Osteocondrodisplasias , Fenotipo , Hermanos , Niño , Femenino , Humanos , Homocigoto , Mutación/genética , Mutación Missense/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Osteocondrodisplasias/diagnóstico , Linaje , Proteínas de Unión al ADN/genéticaRESUMEN
THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.
Asunto(s)
Discapacidad Intelectual , ARN , Estilbenos , Ácidos Sulfónicos , Humanos , Animales , Ratones , ARN/metabolismo , Discapacidad Intelectual/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Procesamiento Postranscripcional del ARN , Transporte de ARN , Mamíferos/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoAsunto(s)
Miasis , Humanos , Miasis/parasitología , Miasis/diagnóstico , Animales , Masculino , Psychodidae/parasitología , FemeninoRESUMEN
The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.
Asunto(s)
Epilepsia , Asesoramiento Genético , Fenotipo , Humanos , Epilepsia/genética , Epilepsia/epidemiología , Epilepsia/diagnóstico , India/epidemiología , Masculino , Femenino , Niño , Preescolar , Lactante , Predisposición Genética a la Enfermedad , Linaje , Edad de Inicio , Estudios de Asociación Genética , Adolescente , Genotipo , Variaciones en el Número de Copia de ADN/genéticaRESUMEN
Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.
Asunto(s)
Proteínas de Ciclo Celular , Quistes , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias , Niño , Humanos , Masculino , Proteínas de Ciclo Celular/genética , Quistes/genética , Quistes/diagnóstico por imagen , Variaciones en el Número de Copia de ADN/genética , Secuenciación del Exoma , Duplicación de Gen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Homocigoto , Imagen por Resonancia Magnética , LinajeRESUMEN
Nucleoporins (NUPs) are a group of transporter proteins that maintain homeostasis of nucleocytoplasmic transport of proteins and ribonucleic acids under physiological conditions. Biallelic pathogenic variants in NUP214 are known to cause susceptibility to acute infection-induced encephalopathy-9 (IIAE9, MIM#618426), which is characterized by severe and early-onset febrile encephalopathy causing neuroregression, developmental delay, microcephaly, epilepsy, ataxia, brain atrophy, and early death. NUP214-related IIAE9 has been reported in eight individuals from four distinct families till date. We identified a novel in-frame deletion, c.202_204del p.(Leu68del), in NUP214 by exome sequencing in a 20-year-old male with episodic ataxia, seizures, and encephalopathy, precipitated by febrile illness. Neuroimaging revealed progressive cerebellar atrophy. In silico predictions show a change in the protein conformation that may alter the downstream protein interactions with the NUP214 N-terminal region, probably impacting the mRNA export. We report this novel deletion in NUP214 as a cause for a late onset and less severe form of IIAE9.
Asunto(s)
Encefalopatía Aguda Febril , Encefalopatías , Epilepsia , Microcefalia , Masculino , Humanos , Adulto Joven , Adulto , Encefalopatías/diagnóstico , Encefalopatías/genética , Epilepsia/genética , Microcefalia/genética , Atrofia , Proteínas de Complejo Poro Nuclear/genéticaRESUMEN
The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.
RESUMEN
THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 facilitates the formation of the Transcription Export complex (TREX) tetramer, composed of four THO monomers. The TREX tetramer supports mammalian mRNA processing that is distinct from yeast TREX dimer functions. Human and mouse TIDS model systems allow novel THOC6-dependent TREX tetramer functions to be investigated. Biallelic loss-of-functon(LOF) THOC6 variants do not influence the expression and localization of TREX members in human cells, but our data suggests reduced binding affinity of ALYREF. Impairment of TREX nuclear export functions were not detected in cells with biallelic THOC6 LOF. Instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing novel insights into THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions that may inform TIDS neuropathology.
RESUMEN
Congenital myasthenic syndromes (CMS) are rare, heterogeneous, and often treatable genetic disorders depending on the underlying molecular defect. We performed a detailed clinical evaluation of seven patients from five unrelated families. Exome sequencing was performed on five index patients. Clinically significant variants were identified in four CMS disease-causing genes: COLQ (3/7), CHRNE (2/7), DOK7 (1/7), and RAPSN (1/7). We identified two novel variants, c.930_933delCATG in DOK7 and c.1016_1032â +â 2dup in CHRNE . A common pathogenic variant, c.955-2A>C, has been identified in COLQ -related CMS patients. Homozygosity mapping of this COLQ variant in patients from two unrelated families revealed that it was located in a common homozygous region of 3.2 Mb on chromosome 3 and was likely to be inherited from a common ancestor. Patients with COLQ variants had generalized muscle weakness, those with DOK7 and RAPSN variants had limb-girdle weakness, and those with CHRNE variants had predominant ocular weakness. Patients with COLQ and DOK7 variants showed improvement with salbutamol and CHRNE with pyridostigmine therapy. This study expands the mutational spectrum and adds a small but significant cohort of CMS patients from India. We also reviewed the literature to identify genetic subtypes of CMS in India.
Asunto(s)
Síndromes Miasténicos Congénitos , Humanos , Albuterol , Pueblo Asiatico/genética , Cromosomas Humanos Par 3 , Síndromes Miasténicos Congénitos/diagnóstico , Síndromes Miasténicos Congénitos/genética , Personas del Sur de Asia/genéticaRESUMEN
Heterozygous disease-causing variants in BCL11B are the basis of a rare neurodevelopmental syndrome with craniofacial and immunological involvement. Isolated craniosynostosis, without systemic or immunological findings, has been reported in one of the 17 individuals reported with this disorder till date. We report three additional individuals harboring de novo heterozygous frameshift variants, all lying in the exon 4 of BCL11B. All three individuals presented with the common findings of this disorder i.e. developmental delay, recurrent infections with immunologic abnormalities and facial dysmorphism. Notably, craniosynostosis of variable degree was seen in all three individuals. We, thus add to the evolving genotypes and phenotypes of BCL11B-related BAFopathy and also review the clinical, genomic spectrum along with the underlying disease mechanisms of this disorder.
Asunto(s)
Craneosinostosis , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Factores de Transcripción/genética , Craneosinostosis/diagnóstico , Craneosinostosis/genética , Mutación del Sistema de Lectura , Fenotipo , Proteínas Supresoras de Tumor/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Proteínas Represoras/genéticaRESUMEN
INTRODUCTION: KCNK18 , a potassium channel subfamily K member 18 (MIM*613655), encodes for TWIK-related spinal cord K+ channel (TRESK) and is important for maintaining neuronal excitability. Monoallelic variants in KCNK18 are known to cause autosomal dominant migraine, with or without aura, susceptibility to, 13 (MIM#613656). Recently, biallelic missense variants in KCNK18 have been reported in three individuals from a non-consanguineous family with intellectual disability, developmental delay, autism spectrum disorder (ASD), and seizure. METHODS: Singleton exome sequencing was performed for the proband after detailed clinical evaluation to identify the disease-causing variants in concordance with the phenotype. RESULTS: We herein report an individual with intellectual disability, developmental delay, ASD, and epilepsy with febrile seizure plus with a novel homozygous stopgain variant, c.499C>T p.(Arg167Ter) in KCNK18 . CONCLUSION: This report further validates KCNK18 as a cause of autosomal recessive intellectual disability, epilepsy, and ASD.
Asunto(s)
Trastorno del Espectro Autista , Epilepsia , Discapacidad Intelectual , Convulsiones Febriles , Humanos , Discapacidad Intelectual/genética , Convulsiones Febriles/genética , Epilepsia/genética , Mutación Missense , Canales de Potasio/genéticaRESUMEN
Arthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts of the body. Neurological and muscular disorders are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Using exome sequencing, we identified homozygous truncating variants in FILIP1 in all patients. FILIP1 is a regulator of filamin homeostasis required for the initiation of cortical cell migration in the developing neocortex and essential for the differentiation process of cross-striated muscle cells during myogenesis. In summary, our data indicate that bi-allelic truncating variants in FILIP1 are causative of a novel autosomal recessive disorder and expand the spectrum of genetic factors causative of arthrogryposis multiplex congenita.
Asunto(s)
Artrogriposis , Contractura , Microcefalia , Humanos , Artrogriposis/genética , Microcefalia/genética , Homocigoto , Fenotipo , Linaje , Proteínas Portadoras/genética , Proteínas del Citoesqueleto/genéticaRESUMEN
Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1-9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5-related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.
RESUMEN
Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term encompassing various inherited neurological disorders characterised by abnormal iron accumulation in basal ganglia. We aimed to study the clinical, radiological and molecular spectrum of disorders with NBIA. All molecular-proven cases of NBIA presented in the last 5 years at 2 tertiary care genetic centres were compiled. Demographic details and clinical and neuroimaging findings were collated. We describe 27 individuals from 20 unrelated Indian families with causative variants in 5 NBIA-associated genes. PLA2G6-associated neurodegeneration (PLAN) was the most common, observed in 13 individuals from 9 families. They mainly presented in infancy with neuroregression and hypotonia. A recurrent pathogenic variant in COASY was observed in two neonates with prenatal-onset severe neurodegeneration. Pathogenic bi-allelic variants in PANK2, FA2H and C19ORF12 genes were observed in the rest, and these individuals presented in late childhood and adolescence with gait abnormalities and extrapyramidal symptoms. No intrafamilial and interfamilial variability were observed. Iron deposition on neuroimaging was seen in only 6/17 (35.3%) patients. A total of 22 causative variants across 5 genes were detected including a multiexonic duplication in PLA2G6. The variants c.1799G > A and c.2370 T > G in PLA2G6 were observed in three unrelated families. In silico assessments of 8 amongst 9 novel variants were also performed. We present a comprehensive compilation of the phenotypic and genotypic spectrum of various subtypes of NBIA from the Indian subcontinent. Clinical presentation of NBIAs is varied and not restricted to extrapyramidal symptoms or iron accumulation on neuroimaging.
Asunto(s)
Trastornos del Movimiento , Malformaciones del Sistema Nervioso , Adolescente , Recién Nacido , Humanos , Niño , Ganglios Basales , Genotipo , Trastornos del Movimiento/patología , Neuroimagen , Hierro , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Proteínas Mitocondriales/genéticaRESUMEN
Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco-abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component. Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS.
Asunto(s)
Anomalías Múltiples , Ano Imperforado , Anomalías Urogenitales , Embarazo , Femenino , Humanos , Síndrome , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Ano Imperforado/diagnóstico , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , FetoRESUMEN
BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.