ASH1L mutation caused seizures and intellectual disability in twin sisters

ASH1L mutations have been identified with variable phenotypes, including intellectual disability, autism spectrum disorder (ASD), and multiple congenital anomalies (MCA). However, the mechanisms underlying this phenotypic variation remain unknown. Here, we present twin sisters exhibiting mild intellectual disability and seizures. Whole-exome sequencing of the family revealed a novel de novo heterozygous sequence variant, NM_018489.2: c.2678dup (p.Lys894*) in exon 3 of ASH1L which was estimated to be pathogenic. Furthermore, we reviewed previously reported ASH1L mutations in order to evaluate genotype-phenotype correlations for ASH1L variants. We found that patients with missense mutations in ASH1L appeared to present with more severe phenotypes and a higher likelihood of ASD than those with truncating mutations. The relationship between phenotype and genotype reported across several patients may help to explain the mechanisms underlying the phenotypic variation commonly observed between ASH1L mutations.     

The phenotypic spectrum of <Emphasis Type="Italic">ARHGEF9</Emphasis> includes intellectual disability,focal epilepsy and febrile seizures

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2–3 years and intellectual disability. Three developed afebrile seizures between age 7–17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.     

A new case of concurrent existence of PRRT2-associated paroxysmal movement disorders with c.649dup variant and 16p11.2 microdeletion syndrome

BackgroundThe PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes.Case reportA 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele.ConclusionsOur case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.     

A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome

BackgroundAutism spectrum disorder is a major neurodevelopmental disorder. Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum.MethodsWe report a case of a male child who presented with global developmental delay, and autism. Additional clinical features in the child were prominent eyes, long palpebral fissures with eversion of lateral third of the lower eyelid, hypoplastic nipples, and persistent fetal fingertip pads. The clinical features were in favor of Kabuki-like syndrome. MRI brain revealed corpus callosal dysgenesis, mild cerebellar para-vermian, and vermian atrophy.ResultsTrio exome sequencing has revealed a novel pathogenic compound heterozygous variant c.145A >T (p.Lys49Ter) and c.224_242del (p.Val85GlufsTer88) in exon 2 of the C12orf57 gene.ConclusionThis is the first case of Temtamy syndrome reported from India with additional novel phenotypic features not reported previously and broadens the phenotypic spectrum of the disorder. In addition, it expands the spectrum of pathogenic variants in the C12orf57 gene.     

Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients

BackgroundIn the last two decades, with the advent of whole-exome and whole-genome sequencing, supplemented with linkage analysis, more than 150 genes responsible for X-linked intellectual disability have been identified. Some genes like NEXMIF remain an enigmatic entity, as often the carrier females show wide phenotypic diversity ranging from completely asymptomatic to severe intellectual disability and drug-resistant epilepsy.MethodsWe report three patients with pathogenic NEXMIF variants from an Indian family. All of them had language predominant developmental delay and later progressed to moderate intellectual disability with autistic features. We also reviewed the previously published reports of patients with pathogenic NEXMIF variants.ResultsTogether with the presented cases, 45 cases (24 symptomatic females) were identified from 15 relevant research items for analysis. Males have demonstrated a more severe intellectual disability and increasingly delayed walking age, autistic features, central hypotonia, and gastroesophageal reflux. In contrast, females have shown a predominant presentation with drug-resistant epilepsy and mild to moderate intellectual impairment. Notably, the affected females demonstrate a higher incidence of myoclonic, absence, and atonic seizures. The majority of the variants reported are nonsense or frameshift mutations, causing loss of function of the NEXMIF gene, while a considerable proportion possesses chromosomal translocations, microdeletions, and duplications.ConclusionsNEXMIF gene mutations should be suspected in all cases of X-linked ID and autism cases in males or even in refractory epilepsy cases in females.     

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures,severe intellectual disability,optic atrophy,muscular hypotonia,and brain abnormalities

Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5‐year‐old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the α_II‐subunit of the voltage‐gated sodium channel Na_v1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A‐linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature

SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.     

Electroencephalographic findings and genetic characterization of two brothers with IQSEC2 pathogenic variant

Two brothers with an IQSEC2 pathogenic variant presented with early onset intellectual disability, intractable epileptic seizures, autism spectrum disorders, postnatal microcephalus and slowly progressive rigid-spasticity. Their epileptic seizures were characterized by intractability, early onset epileptic spasms, and then clusters of tonic/tonic-clonic seizures, exacerbated by valproate. Electroencephalography showed periodic discharges, including periodic high voltage slow complexes and burst-suppression activity.Whole exome sequencing, using DNA from peripheral blood of both brothers, identified a pathogenic variant, c.2776 C > T, p.(Arg 926*) in exon 9 of IQSEC2 (NM 001111125.3). Their parents and another brother did not have this variant, which may suggest that maternal gonadal mosaicism is the most likely mechanism.     

Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation

The phenotype attributed to MECP2 mutations continues to expand. In addition to classic and variant Rett syndrome, phenotypes include non‐specific intellectual disability and autism spectrum disorder in females, and fatal neonatal encephalopathy in males. One particular phenotype of parkinsonism, pyramidal signs, and neuropsychiatric symptoms (PPM‐X) has been described only in males. We report on the first female with the A140V MECP2 mutation presenting with late onset cognitive regression, pyramidal symptoms, parkinsonism, and bipolar symptoms. This finding emphasizes the need to consider MECP2 sequencing in females with non‐classic Rett phenotypes, particularly those with intellectual disability and neuropsychiatric features.     

A de novo CHD3 variant in a child with intellectual disability,autism, joint laxity,and dysmorphisms

BackgroundChromodomain helicase DNA-binding (CHD) proteins play important roles in developmental processes. CHD3, a member of the CHD family of proteins, was reported to be a cause of a neurodevelopmental syndrome by Snijders Blok et al., but only a small number of probands have been reported.Case reportThe patient was a 9-year-old female with severe intellectual disability, speech impairment, autism, joint laxity and dysmorphisms. Whole exome sequencing revealed a de novo missense variant in CHD3 (NM_001005273:exon18: c.2896C > T:p.R966W).ConclusionWe report a case with a pathogenic variant in the CHD3 gene. Our report indicates that CHD3 analysis is helpful for diagnosis of the cases with neurodevelopmental disorders, joint laxity, and coarse facial phenotype.     

Mild epileptic phenotype associates with de novo eef1a2 mutation: Case report and review

BackgroundMutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been recently shown to cause epileptic encephalopathy (MIM # 616409 EIEE33) associated with neurodevelopmental disorders such as intellectual disability, autistic spectrum disorder, hypotonia and dysmorphic facial features. EEF1A2 protein is involved in protein synthesis, suppression of apoptosis, regulation of actin function and cytoskeletal structure. To date, only sixteen patients with EEF1A2 mutations have been reported.Case reportWe described a new case, a boy with severe intellectual disability with absent speech, autistic spectrum disorder, mild dysmorphic facial features, failure to thrive and epilepsy associated to a de novo heterozygous missense mutation in EEF1A2 (c.364G>A; p.Glu122Lys) identified by next generation sequencing; it was already reported in other studies. Most clinical features are shared by all individuals with EEF1A2 mutation, but unlike others reports our patient showed a mild epileptic phenotype: epilepsy developed in late infancy and was well-controlled with antiepileptic drugs. Moreover, at the onset of epilepsy, interictal wake/sleep electroencephalograms showed typical pattern that disappeared with age.ConclusionThis report focused that EEF1A2 mutations should be considered not only in patients with epileptic encephalopathy, but also in those with less severe epilepsy. A typical EEG pattern may be a biomarker for EEF1A2 mutation, but further investigations and longitudinal clinical observations are required.     

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach

The hypothetical ‘AXAS'' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.     

Epilepsy and Autism: Neurodevelopmental Perspective

Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.     

Phenotypic spectrum and genetics of SCN2A‐related disorders,treatment options,and outcomes in epilepsy and beyond

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self‐limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later‐onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.     

Defining the phenotype of FHF1 developmental and epileptic encephalopathy

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.     

Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci

Despite tremendous progress through next generation sequencing technologies, familial focal epilepsies are insufficiently understood. We sought to identify the genetic basis in multiplex Palestinian families with familial focal epilepsy with variable foci (FFEVF). Family I with 10 affected individuals and Family II with five affected individuals underwent detailed phenotyping over three generations. The phenotypic spectrum of the two families varied from nonlesional focal epilepsy including nocturnal frontal lobe epilepsy to severe structural epilepsy due to hemimegalencephaly. Whole‐exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38‐kb deletion encompassing eight exons (exons 8‐15) and the 3′‐untranslated region of the NPRL3 gene in Family I, and a de novo nonsense variant c.1063C>T, p.Gln355* in Family II. Furthermore, we identified a truncating variant in the PDCD10 gene in addition to the NPRL3 variant in a patient with focal epilepsy from Family I. The individual also had developmental delay and multiple cerebral cavernomas, possibly demonstrating a digenic contribution to the individual's phenotype. Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants.     

Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.