Publications by authors named "Heather C Mefford"

177 Publications

Diagnostic Considerations in the Epilepsies-Testing Strategies, Test Type Advantages, and Limitations.

Neurotherapeutics 2021 07 16;18(3):1468-1477. Epub 2021 Sep 16.

Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, 98105, USA.

The role of genetics in epilepsy has been recognized for a long time. Over the past decade, genome-wide technologies have identified numerous genes and variants associated with epilepsy. In the clinical setting, a myriad of genetic testing options are available, and a subset of specific genetic diagnoses have management implications. Furthermore, genetic testing can be a dynamic process. As a result, fundamental knowledge about genetics and genomics has become essential for all specialists. Here, we review current knowledge of the genetic contribution to various types of epilepsy, provide an overview of types of genetic variants, and discuss genetic testing options and their diagnostic yield. We also consider advantages and limitations of testing approaches.
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http://dx.doi.org/10.1007/s13311-021-01121-7DOI Listing
July 2021

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Brain 2021 Oct;144(9):2659-2669

Division of Genetic Medicine, Department of Paediatrics, University of Washington, Seattle, WA 98195, USA.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.
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http://dx.doi.org/10.1093/brain/awab124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557332PMC
October 2021

Genetic convergence of developmental and epileptic encephalopathies and intellectual disability.

Dev Med Child Neurol 2021 Dec 11;63(12):1441-1447. Epub 2021 Jul 11.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.

Aim: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only.

Method: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male).

Results: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10 , odds ratio 37.22, 95% confidence interval 8.60-337.0).

Interpretation: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause. What this paper adds A subset of genes are more commonly implicated in epilepsy than other neurodevelopmental disorders. GRIN2B and SCN2A are implicated in intellectual disability and epilepsy independently.
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http://dx.doi.org/10.1111/dmcn.14989DOI Listing
December 2021

Targeted long-read sequencing identifies missing disease-causing variation.

Am J Hum Genet 2021 08 2;108(8):1436-1449. Epub 2021 Jul 2.

Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387463PMC
August 2021

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

Ann Neurol 2021 08 13;90(2):274-284. Epub 2021 Jul 13.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia.

Objective: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.

Methods: Using 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.

Results: We identify de novo missense variants in the STK domain in 11 individuals, including 2 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 seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients 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 wild-type. 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.

Interpretation: In 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. ANN NEUROL 2021;90:274-284.
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http://dx.doi.org/10.1002/ana.26147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324566PMC
August 2021

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot.

Genet Med 2021 10 10;23(10):1952-1960. Epub 2021 Jun 10.

University of Nottingham, Queen's Medical Centre, Nottingham, UK.

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10).

Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.
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http://dx.doi.org/10.1038/s41436-021-01212-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486653PMC
October 2021

Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder.

Neurol Genet 2021 Apr 18;7(2):e579. Epub 2021 Mar 18.

Research Institute of the McGill University Health Centre (K.M.), Montreal, PQ; Division of Child Neurology (K.M.), Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, PQ; Department of Neurology & Neurosurgery (K.M.), Montreal Children's Hospital, McGill University, Montreal, PQ; Child Neurology and Psychiatry (C.M.), Salesi Pediatric Hospital, United Hospitals of Ancona, Ancona, Italy; Division of Genetic Medicine (G.L.C., J.N., H.C.M.), Department of Pediatrics, University of Washington, Seattle, WA; Department of Neurology (A.M.), Great Ormond Street Hospital for Children, London, UK; Developmental Neurosciences Programme (A.M.), UCL Great Ormond Street Institute of Child Health, London, UK; Neurology Network Melbourne (J.P.), Melbourne, Victoria, Australia; Murdoch Children's Research Institute (C.S., I.E.S.), Parkville, Victoria, Australia; Department of Paediatrics and Child Health (T.S.), School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; Division of Neurology (S.M.), Department of Pediatrics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Neurology Unit and Neurogenetic Laboratories (C.B., A.R., R.G.), Meyer Children's Hospital, Florence, Italy; Department of Clinical Genetics (R.H.S.), Great Ormond Street Hospital, London, UK; Epilepsy Research Centre (I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; Department of Paediatrics (I.E.S.), Royal Children's Hospital, The University of Melbourne, Parkville, Victoria, Australia; and The Florey Institute of Neuroscience and Mental Health (I.E.S.), Heidelberg, Victoria, Australia.

Objective: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia.

Methods: We performed phenotyping on patients with deletions, duplications, or point mutations and a history of seizures.

Results: Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days-13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance.

Conclusions: disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.
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http://dx.doi.org/10.1212/NXG.0000000000000579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075573PMC
April 2021

Developmental and epileptic encephalopathy: Personal utility of a genetic diagnosis for families.

Epilepsia Open 2021 03 19;6(1):149-159. Epub 2021 Jan 19.

Department of Paediatrics and Child Health University of Otago Wellington New Zealand.

Objectives: Identifying genetic pathogenic variants improves clinical outcomes for children with developmental and epileptic encephalopathy (DEE) by directing therapy and enabling accurate reproductive and prognostic information for families. We aimed to explore the additional personal utility of receiving a genetic diagnosis for families.

Methods: Semi-structured interviews were conducted with fifteen families of children with a DEE who had received a genetic diagnosis. The interviews stimulated discussion focusing on the impact of receiving a genetic diagnosis for the family. Interview transcripts were analyzed using the six-step systematic process of interpretative phenomenological analysis (IPA).

Results: Three key themes were identified: "Importance of the label," "Relief to end the diagnostic journey," and "Factors that influence personal utility." Families reported that receiving a genetic label improved their knowledge about the likely trajectory of the DEE, increased their hope for the future, and helped them communicate with others. The relief of finally having an answer for the cause of their child's DEE alleviated parental guilt and self-blame as well as helped families to process their grief and move forward. Delay in receipt of a genetic diagnosis diluted its psychological impact.

Significance: To date, the factors associated with the personal utility of a genetic diagnosis for DEEs have been under appreciated. This study demonstrates that identifying a genetic diagnosis for a child's DEE can be a psychological turning point for families. A genetic result has the potential to set these families on an adaptive path toward better quality of life through increased understanding, social connection, and support. Early access to genetic testing is important as it not only increases clinical utility, but also increases personal utility with early mitigation of family stress, trauma, and negative experiences.
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http://dx.doi.org/10.1002/epi4.12458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918330PMC
March 2021

The severe epilepsy syndromes of infancy: A population-based study.

Epilepsia 2021 02 21;62(2):358-370. Epub 2021 Jan 21.

Department of Neurology, Royal Children's Hospital, Melbourne, Vic, Australia.

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.

Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.

Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased.

Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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http://dx.doi.org/10.1111/epi.16810DOI Listing
February 2021

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.

Genet Med 2021 05 20;23(5):881-887. Epub 2021 Jan 20.

Duke University Health System, Durham, NC, USA.

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.

Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.

Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.

Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
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http://dx.doi.org/10.1038/s41436-020-01076-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107131PMC
May 2021

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

Epilepsia 2021 02 7;62(2):325-334. Epub 2021 Jan 7.

Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.

Objective: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis.

Methods: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants.

Results: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired.

Significance: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.
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http://dx.doi.org/10.1111/epi.16761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898319PMC
February 2021

Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype.

Mol Genet Genomic Med 2021 01 22;9(1):e1542. Epub 2020 Dec 22.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Background: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy.

Methods: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients.

Results: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy.

Conclusions: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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http://dx.doi.org/10.1002/mgg3.1542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963417PMC
January 2021

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Genet Med 2021 04 10;23(4):653-660. Epub 2020 Dec 10.

Institute of Child Health, University Collge London, London, UK.

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
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http://dx.doi.org/10.1038/s41436-020-01020-wDOI Listing
April 2021

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Epilepsia 2021 01 6;62(1):e13-e21. Epub 2020 Dec 6.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
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http://dx.doi.org/10.1111/epi.16784DOI Listing
January 2021

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Am J Hum Genet 2020 10 4;107(4):727-742. Epub 2020 Sep 4.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536580PMC
October 2020

Poison exons in neurodevelopment and disease.

Curr Opin Genet Dev 2020 12 29;65:98-102. Epub 2020 Jun 29.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA. Electronic address:

Poison exons are naturally occurring, highly conserved alternative exons that contain a premature termination codon. Inclusion of a poison exon in a transcript targets the transcript for nonsense mediated decay, decreasing the amount of protein produced. Poison exons are proposed to play an important role in tissue-specific expression, development and autoregulation of gene expression. Recently, several studies that performed systematic investigations of alternative splicing in the brain have highlighted the abundance of transcripts containing poison exons, some of which are spliced in a cell type-specific manner. Pathogenic variants in or near poison exons that result in aberrant splicing have been identified in several genes including FLNA, SCN1A and SNRPB. Improved understanding of the role of poison exons in development and disease may present opportunities to solve previously undiagnosed disease and to develop therapeutic approaches in the future.
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http://dx.doi.org/10.1016/j.gde.2020.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042789PMC
December 2020

The Impact of Rapid Exome Sequencing on Medical Management of Critically Ill Children.

J Pediatr 2020 Nov 15;226:202-212.e1. Epub 2020 Jun 15.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA; Brotman Baty Institute for Precision Medicine, Seattle, WA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA. Electronic address:

Objectives: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population.

Study Design: We implemented a process to provide clinical-grade rES to eligible children at a single institution. Eligibility included (a) recommendation of rES by a consulting geneticist, (b) monogenic disorder suspected, (c) rapid diagnosis predicted to affect inpatient management, (d) pretest counseling provided by an appropriate provider, and (e) unanimous approval by a committee of 4 geneticists. Trio exome sequencing was sent to a reference laboratory that provided verbal report within 7-10 days. Clinical outcomes related to rES were prospectively collected. Input from geneticists, genetic counselors, pathologists, neonatologists, and critical care pediatricians was collected to identify changes in management related to rES.

Results: There were 54 patients who were eligible for rES over a 34-month study period. Of these patients, 46 underwent rES, 24 of whom (52%) had at least 1 change in management related to rES. In 20 patients (43%), a molecular diagnosis was achieved, demonstrating that nondiagnostic exomes could change medical management in some cases. Overall, 84% of patients were under 1 month old at rES request and the mean turnaround time was 9 days.

Conclusions: rES testing has a significant impact on the management of critically ill children with suspected monogenic disease and should be considered standard of care for tertiary institutions who can provide coordinated genetics expertise.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736066PMC
November 2020

Phenotype to Genotype and Back Again.

Epilepsy Curr 2020 Mar-Apr;20(2):88-89. Epub 2020 Feb 17.

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http://dx.doi.org/10.1177/1535759720901734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160881PMC
February 2020

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.

Am J Hum Genet 2020 05 9;106(5):623-631. Epub 2020 Apr 9.

Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA. Electronic address:

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212259PMC
May 2020

Recent advances in epilepsy genomics and genetic testing.

F1000Res 2020 12;9. Epub 2020 Mar 12.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, 98105, USA.

Developmental and epileptic encephalopathies (DEEs) are a group of severe, early onset epilepsies characterized by refractory seizures, developmental delay or regression associated with ongoing epileptic activity, and generally poor prognosis. DEE is genetically and phenotypically heterogeneous, and there is a plethora of genetic testing options to investigate the rapidly growing list of epilepsy genes. However, more than 50% of patients with DEE remain without a genetic diagnosis despite state-of-the-art genetic testing. In this review, we discuss the major advances in epilepsy genomics that have surfaced in recent years. The goal of this review is to reach a larger audience and build a better understanding of pathogenesis and genetic testing options in DEE.
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http://dx.doi.org/10.12688/f1000research.21366.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076331PMC
July 2020

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.

Hum Mutat 2020 07 6;41(7):1263-1279. Epub 2020 Apr 6.

Department of Genetics, Utrecht University, Utrecht, The Netherlands.

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.
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http://dx.doi.org/10.1002/humu.24015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292794PMC
July 2020

Inherited RORB pathogenic variants: Overlap of photosensitive genetic generalized and occipital lobe epilepsy.

Epilepsia 2020 04 12;61(4):e23-e29. Epub 2020 Mar 12.

Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Victoria, Australia.

Variants in RORB have been reported in eight individuals with epilepsy, with phenotypes ranging from eyelid myoclonia with absence epilepsy to developmental and epileptic encephalopathies. We identified novel RORB variants in 11 affected individuals from four families. One was from whole genome sequencing and three were from RORB screening of three epilepsy cohorts: developmental and epileptic encephalopathies (n = 1021), overlap of generalized and occipital epilepsy (n = 84), and photosensitivity (n = 123). Following interviews and review of medical records, individuals' seizure and epilepsy syndromes were classified. Three novel missense variants and one exon 3 deletion were predicted to be pathogenic by in silico tools, not found in population databases, and located in key evolutionary conserved domains. Median age at seizure onset was 3.5 years (0.5-10 years). Generalized, predominantly absence and myoclonic, and occipital seizures were seen in all families, often within the same individual (6/11). All individuals with epilepsy were photosensitive, and seven of 11 had cognitive abnormalities. Electroencephalograms showed generalized spike and wave and/or polyspike and wave. Here we show a striking RORB phenotype of overlap of photosensitive generalized and occipital epilepsy in both individuals and families. This is the first report of a gene associated with this overlap of epilepsy syndromes.
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http://dx.doi.org/10.1111/epi.16475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363501PMC
April 2020

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

Neuron 2020 04 24;106(2):237-245.e8. Epub 2020 Feb 24.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, VIC, Australia; Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne 3052, VIC, Australia; Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne 3084, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne 3052, VIC, Australia.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.
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http://dx.doi.org/10.1016/j.neuron.2020.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357395PMC
April 2020

Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects.

Epilepsy Curr 2020 Jan-Feb;20(1_suppl):23S-30S. Epub 2020 Jan 22.

Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy-one-third of patients-emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.
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http://dx.doi.org/10.1177/1535759719895279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031805PMC
January 2020
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