scholarly journals Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

2019 ◽  
Author(s):  
Norine Voisin ◽  
Rhonda E. Schnur ◽  
Sofia Douzgou ◽  
Susan M. Hiatt ◽  
Cecilie F. Rustad ◽  
...  
Keyword(s):  
De Novo ◽  
Horseshoe Kidney ◽  
Epileptic Encephalopathy ◽  
Causative Role ◽  
Transactivation Domain ◽  
Elongation Complex ◽  
Autosomal Dominant Disorder ◽  
Pathological Effect ◽  
Missense Variants ◽  
Mesomelic Dysplasia

AbstractThe ALF transcription factor paralogs,AFF1, AFF2, AFF3andAFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe a new autosomal dominant disorder associated withde novomissense variants in the degron of AFF3, a nine amino acid sequence important for its degradation. Consistent with a causative role ofAFF3variants, the mutated AFF3 proteins show reduced clearance. Ten affected individuals were identified, and present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoeKIdney, NS forNievergelt/Savarirayan type of mesomelic dysplasia, S forSeizures, H forHypertrichosis, I forIntellectual disability and P forPulmonary involvement), partially overlapping theAFF4associated CHOPS syndrome. An eleventh individual with a microdeletion encompassing only the transactivation domain and degron motif ofAFF3exhibited overlapping clinical features. A zebrafish overexpression model that shows body axis anomalies provides further support for the pathological effect of increased amount of AFF3 protein.Whereas homozygousAff3knockout mice display skeletal anomalies, kidney defects, brain malformation and neurological anomalies, knock-in animals modeling the microdeletion and the missense variants identified in affected individuals presented with lower mesomelic limb deformities and early lethality, respectively.Transcriptome analyses as well as the partial phenotypic overlap of syndromes associated withAFF3andAFF4variants suggest that ALF transcription factors are not redundant in contrast to what was previously suggested

scholarly journals GNAO1 encephalopathy

2017 ◽  
Vol 3 (2) ◽  
pp. e143 ◽  
Author(s):  
Federica Rachele Danti ◽  
Serena Galosi ◽  
Marta Romani ◽  
Martino Montomoli ◽  
Keren J. Carss ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
De Novo ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Cerebral Atrophy ◽  
Epileptic Encephalopathy ◽  
Causative Role ◽  
Diffuse Astrocytoma ◽  
Who Grade ◽  
Wide Range

Objective:To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease.Methods:We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques.Results:Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.Conclusions:Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

scholarly journals The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

2018 ◽  
Author(s):  
Moritz Hebebrand ◽  
Ulrike Hüffmeier ◽  
Steffen Uebe ◽  
Arif B. Ekici ◽  
Cornelia Kraus ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Clinical Features ◽  
De Novo ◽  
Three Dimensional ◽  
Clinical Information ◽  
Amino Acid Position ◽  
Terminal Region ◽  
Autosomal Dominant Disorder ◽  
Human Phenotype ◽  
Missense Variants

ABSTRACTBackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (70%), although reporting was incomplete in the different studies. We identified a total of 121 distinct variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein modelling, 38.6% of all disease causing variants including those in the C-terminal region are predicted to affect binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

scholarly journals Loss–of–function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

2021 ◽  
Author(s):  
Johanna Krueger ◽  
Julian Schubert ◽  
Josua Kegele ◽  
Audrey Labalme ◽  
Miaomiao Mao ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Surface Expression ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
K Channel ◽  
Loss Of Function ◽  
Normal Surface ◽  
Missense Variants

Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

scholarly journals Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

2019 ◽  
Author(s):  
Anne H O'Donnell-Luria ◽  
Lynn S Pais ◽  
Victor Faundes ◽  
Jordan C Wood ◽  
Abigail Sveden ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Mild Intellectual Disability ◽  
Negative Effects ◽  
Missense Variants ◽  
Neurodevelopmental Abnormalities ◽  
Almost All ◽  
Gastrointestinal Abnormalities

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

scholarly journals Pathogenic MAST3 variants in the STK domain are associated with epilepsy

2021 ◽  
Author(s):  
Egidio Spinelli ◽  
Kyle R Christensen ◽  
Emily Bryant ◽  
Amy Schneider ◽  
Jennifer Rakotomamonjy ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Prenatal Development ◽  
Epileptic Encephalopathy ◽  
Patient Specific ◽  
Gain Of Function ◽  
Missense Variants ◽  
Excitatory Neurons

AbstractObjectiveThe MAST family of microtubule-associated serine-threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.MethodsUsing exome sequencing we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells.ResultsWe identify de novo missense variants in the STK domain in 11 individuals, including two recurrent variants p.G510S (n=5) and p.G515S (n=3). All 11 individuals had Developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at < 2 years of age. All patients developed multiple seizures types, while 9/11 had seizures triggered by fever and 9/11 had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wildtype. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally.InterpretationIn summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex.

Sign in / Sign up

Export Citation Format

Share Document