Search

PurposeARF1was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum ofARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) withARF1variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) inARF1were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role ofARF1in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the

Early infantile epileptic encephalopathies (EIEEs) are a group of disorders with seizures presenting early in life. EIEE is associated with significant mortality and morbidity. Approximately 50 percent of the affected patients die in infancy. Those who survive develop therapy-resistant epilepsy and significant developmental delays1. Structural brain lesions, metabolic disorders and genetic mutations, including KCNQ2, have been linked to EIEE1, 2,3. Here, we report two neonates with EIEE due to KCNQ2 mutations, one with a novel mutation diagnosed through the rapid genomic sequencing program at Rady Children’s Institute for Genomic Medicine (RCIGM) and one diagnosed classically, and demonstrate how rapid diagnosis positively impacted care.

Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism.We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system.We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction.Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.

To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).Whole exome sequencing was performed on 2 parent-child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions.The same de novo mutation (c.1252CT, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176GA, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in β-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect.FDFM is likely caused by gain-of-function mutations in different domains of ADCY5-the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.