Publications by authors named "Mitsuhiro Kato"

186 Publications

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 Feb 24. Epub 2021 Feb 24.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
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http://dx.doi.org/10.1002/ajmg.a.62138DOI Listing
February 2021

Limb-clasping, cognitive deficit and increased vulnerability to kainic acid-induced seizures in neuronal glycosylphosphatidylinositol deficiency mouse models.

Hum Mol Genet 2021 Feb 19. Epub 2021 Feb 19.

Laboratory of Social Neural Networks, Center for Social Neural Networks, University of Tsukuba, Tsukuba 305-8577, Japan.

Post-translational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, more than 150 human GPI anchored proteins have been discovered and about 30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko), or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid (KA)-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities.
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http://dx.doi.org/10.1093/hmg/ddab052DOI Listing
February 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Authors:
Joery den Hoed Elke de Boer Norine Voisin Alexander J M Dingemans Nicolas Guex Laurens Wiel Christoffer Nellaker Shivarajan M Amudhavalli Siddharth Banka Frederique S Bena Bruria Ben-Zeev Vincent R Bonagura Ange-Line Bruel Theresa Brunet Han G Brunner Hui B Chew Jacqueline Chrast Loreta Cimbalistienė Hilary Coon Emmanuèlle C Délot Florence Démurger Anne-Sophie Denommé-Pichon Christel Depienne Dian Donnai David A Dyment Orly Elpeleg Laurence Faivre Christian Gilissen Leslie Granger Benjamin Haber Yasuo Hachiya Yasmin Hamzavi Abedi Jennifer Hanebeck Jayne Y Hehir-Kwa Brooke Horist Toshiyuki Itai Adam Jackson Rosalyn Jewell Kelly L Jones Shelagh Joss Hirofumi Kashii Mitsuhiro Kato Anja A Kattentidt-Mouravieva Fernando Kok Urania Kotzaeridou Vidya Krishnamurthy Vaidutis Kučinskas Alma Kuechler Alinoë Lavillaureix Pengfei Liu Linda Manwaring Naomichi Matsumoto Benoît Mazel Kirsty McWalter Vardiella Meiner Mohamad A Mikati Satoko Miyatake Takeshi Mizuguchi Lip H Moey Shehla Mohammed Hagar Mor-Shaked Hayley Mountford Ruth Newbury-Ecob Sylvie Odent Laura Orec Matthew Osmond Timothy B Palculict Michael Parker Andrea K Petersen Rolph Pfundt Eglė Preikšaitienė Kelly Radtke Emmanuelle Ranza Jill A Rosenfeld Teresa Santiago-Sim Caitlin Schwager Margje Sinnema Lot Snijders Blok Rebecca C Spillmann Alexander P A Stegmann Isabelle Thiffault Linh Tran Adi Vaknin-Dembinsky Juliana H Vedovato-Dos-Santos Samantha A Schrier Vergano Eric Vilain Antonio Vitobello Matias Wagner Androu Waheeb Marcia Willing Britton Zuccarelli Usha Kini Dianne F Newbury Tjitske Kleefstra Alexandre Reymond Simon E Fisher Lisenka E L M Vissers

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
February 2021

Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3.

Am J Med Genet A 2021 Jan 27. Epub 2021 Jan 27.

Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.
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http://dx.doi.org/10.1002/ajmg.a.62084DOI Listing
January 2021

Association of early-onset epileptic encephalopathy with involuntary movements - Case series and literature review.

Epilepsy Behav Rep 2021 17;15:100417. Epub 2020 Dec 17.

Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.

Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent seizures, severe developmental delay and accompanying involuntary movements. We detected four genetic mutations, including and variants. The involuntary movements were drug-resistant. However, pallidal electrocoagulation followed by gabapentin were partially effective in treating chorea and ballismus of the extremities in patients with variants, and perampanel partially suppressed seizures and involuntary movements in one patient with a variant. Movement disorders are common to many neurodevelopmental disorders, including a variety of EOEEs. Although we could not establish a definitive correlation using genetic variants in patients with EOEE and movement disorders, involuntary movements in patients with EOEEs may be a key diagnostic finding. The usage of genetic variants could prove beneficial in the future as more patients are investigated with epileptic-dyskinetic encephalopathies.
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http://dx.doi.org/10.1016/j.ebr.2020.100417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808918PMC
December 2020

Interleukin-1β in peripheral monocytes is associated with seizure frequency in pediatric drug-resistant epilepsy.

J Neuroimmunol 2021 Mar 7;352:577475. Epub 2021 Jan 7.

Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku, Tokyo 160-0023, Japan.

In this study, we assessed circulating immune cells and plasma cytokine levels in 15 pediatric patients with drug-resistant epilepsy (DRE). DRE patients had a significantly higher percentage of CD14 monocytes positive for IL-1β, IL-1 receptor antagonist, IL-6, and TNF-α than controls. Significantly higher intracellular levels of IFN-γ in CD4 T cells and NK cells were also found in DRE patients. The level of IL-1β CD14 monocytes correlated with seizure frequency, and intracellular levels of IFN-γ in NKT-like cells were negatively correlated with the duration of epilepsy. Peripheral immune cells might be involved in the pathogenesis of DRE.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577475DOI Listing
March 2021

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Brain Dev 2021 Apr 9;43(4):505-514. Epub 2021 Jan 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.

Results: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.

Conclusion: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
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http://dx.doi.org/10.1016/j.braindev.2020.12.006DOI Listing
April 2021

Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia.

Hum Genome Var 2020 Dec 3;7(1):43. Epub 2020 Dec 3.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama, 236-0004, Japan.

Pathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.
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http://dx.doi.org/10.1038/s41439-020-00131-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713383PMC
December 2020

Clinical variations of epileptic syndrome associated with PACS2 variant.

Brain Dev 2021 Feb 23;43(2):343-347. Epub 2020 Nov 23.

Department of Pediatrics, Showa University School of Medicine, Japan.

Background: Recent studies have suggested that two PACS2 pathogenic variants, c.625G > A (p.Glu209Lys) and c.631G > A (p.Glu211Lys), have been causally linked to the characteristic developmental and epileptic encephalopathy, including autistic behaviors, hypotonia, cerebellar dysgenesis and facial dysmorphism. Their seizures appear most difficult to control in neonatal and infant period, but improve after the first year of life. We herein report three patients with the same PACS2 variant, c.625G > A (p.Glu209Lys), showing different characteristics from previous reports.

Case Report: Case 1, a 2-year-old girl, developed frequent tonic convulsions 2 weeks after birth. Brain magnetic resonance imaging showed a decrease in posterior periventricular white matter volume, an enlargement of the inferior horn of lateral ventricles and old subependymal hemorrhage. Epilepsy is now controlled with antiepileptic drugs. Case 2, a 12-year-old girl, developed generalized tonic convulsions 3 days after birth. Although epilepsy had been controlled since the age of 4, she developed Lennox-Gastaut syndrome at 9 years old. Case 3, a 3-year-old girl, developed tonic convulsions 3 days after birth. She now exhibits normal psychomotor development, and epilepsy is controlled without medicine.

Conclusion: PACS2-related epileptic syndrome presents variable phenotypes than previously reported. We think that our findings expand the clinical spectrum of this disease, and provide important information about the differential diagnosis of neonatal-onset epileptic syndrome.
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http://dx.doi.org/10.1016/j.braindev.2020.10.006DOI Listing
February 2021

Polymicrogyria with calcification in Pallister-Killian syndrome detected by microarray analysis.

Brain Dev 2021 Mar 21;43(3):448-453. Epub 2020 Nov 21.

Department of Child Neurology, NHO Nishiniigata Chuo Hospital, 1-14-1 Masago, Nishi-ku, Niigata 950-2085, Japan. Electronic address:

Background: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures.

Results: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses.

Conclusion: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.
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http://dx.doi.org/10.1016/j.braindev.2020.11.003DOI Listing
March 2021

Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a variant.

Neurol Genet 2020 Dec 8;6(6):e527. Epub 2020 Oct 8.

Department of Pediatrics (Y.S., T. Mizuno, K.M.), Tokyo Medical and Dental University, Yushima, Bunkyo-ku; Home Care Clinic for Children Aozora Sumida (H.I.), Higashikomagata, Sumida-ku, Tokyo; Department of Pediatrics (M.K.), Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo; Department of Human Genetics (M.N., T. Mizuguchi, N.M.), Yokohama City University Graduate School of Medicine, Fukuura, Kanazawa-ku, Yokohama; Department of Biochemistry (M.N.), Hamamatsu University School of Medicine, Handayama, Higashi-ku Hamamatsu; and Present Address: Department of Pediatrics (Y.S.), Soka Municipal Hospital, Soka, Soka-Shi, Saitama-Ken, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577532PMC
December 2020

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.

Hum Mutat 2021 Jan 10;42(1):66-76. Epub 2020 Nov 10.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.
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http://dx.doi.org/10.1002/humu.24130DOI Listing
January 2021

Comparison of an Immunochromatographic Assay Kit with DAS-ELISA for Large-Scale Diagnosis and Molecular Discrimination of Satsuma Dwarf Virus Collected from Citrus Orchards.

Plant Pathol J 2020 Oct;36(5):509-514

Shizuoka Prefectural Research Institute of Agriculture and Forestry, Fruit Tree Research Center, Mobata, Shimizu, Shizuoka 424-0101, Japan.

Satsuma dwarf virus (SDV) seriously damages citrus production by reducing the quality and yield of fruit. To avoid contamination with SDV, mother trees are checked to be SDV-free in advance of nursery tree distribution. In this study, we compared an immunochromatographic assay (ICA) kit with double-antibody sandwich enzyme-linked immunosorbent assay (DASELISA) for large-scale diagnosis of SDV in orchardgrown trees in Shizuoka Prefecture, Japan. The two methods gave conflicting results for 11 of 1,705 samples, all of which were negative by DAS-ELISA but positive by ICA. The samples scored as positive by either DASELISA or ICA were analyzed by reverse transcription polymerase chain reaction and all were confirmed to be positive. These results validate the use of ICA as a screening method for large-scale diagnosis. Strain discrimination revealed that 16 of 22 isolates belonged to SDV, while citrus mosaic virus (CiMV) infection only and co-infection (SDV and CiMV) were in a minority.
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http://dx.doi.org/10.5423/PPJ.NT.06.2020.0096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542029PMC
October 2020

Clinical and genetic characteristics of patients with Doose syndrome.

Epilepsia Open 2020 Sep 23;5(3):442-450. Epub 2020 Jul 23.

Department of Pediatrics Showa University School of Medicine Tokyo Japan.

Objective: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome.

Methods: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant.

Results: We newly identified four variants: and missense variants and microdeletions at 2q24.2 involving and Xp22.31 involving . Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology.

Significance: MAE patients had genetic heterogeneity, and and emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
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http://dx.doi.org/10.1002/epi4.12417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469791PMC
September 2020

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients.

J Inherit Metab Dis 2020 09 14;43(5):1121-1130. Epub 2020 May 14.

AADC Research Trust, Caterham, UK.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non-motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose-limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.
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http://dx.doi.org/10.1002/jimd.12247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540529PMC
September 2020

De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms.

J Hum Genet 2020 Sep 27;65(9):727-734. Epub 2020 Apr 27.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.
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http://dx.doi.org/10.1038/s10038-020-0758-2DOI Listing
September 2020

Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities.

Am J Hum Genet 2020 01 12;106(1):13-25. Epub 2019 Dec 12.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

MN1 was originally identified as a tumor-suppressor gene. Knockout mouse studies have suggested that Mn1 is associated with craniofacial development. However, no MN1-related phenotypes have been established in humans. Here, we report on three individuals who have de novo MN1 variants that lead to a protein lacking the carboxyl (C) terminus and who presented with severe developmental delay, craniofacial abnormalities with specific facial features, and structural abnormalities in the brain. An in vitro study revealed that the deletion of the C-terminal region led to increased protein stability, an inhibitory effect on cell proliferation, and enhanced MN1 aggregation in nuclei compared to what occurred in the wild type, suggesting that a gain-of-function mechanism is involved in this disease. Considering that C-terminal deletion increases the fraction of intrinsically disordered regions of MN1, it is possible that altered phase separation could be involved in the mechanism underlying the disease. Our data indicate that MN1 participates in transcriptional regulation of target genes through interaction with the transcription factors PBX1, PKNOX1, and ZBTB24 and that mutant MN1 impairs the binding with ZBTB24 and RING1, which is an E3 ubiquitin ligase. On the basis of our findings, we propose the model that C-terminal deletion interferes with MN1's interaction molecules related to the ubiquitin-mediated proteasome pathway, including RING1, and increases the amount of the mutant protein; this increase leads to the dysregulation of MN1 target genes by inhibiting rapid MN1 protein turnover.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042485PMC
January 2020

Phenotype-genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms.

Brain Dev 2020 Feb 15;42(2):199-204. Epub 2019 Nov 15.

Department of Pediatric Neurology, Miyagi Children's Hospital Hospital, Sendai 989-3126, Japan. Electronic address:

We report the first three Japanese patients with missense variants in the GNB1 gene. Patients exhibited severe dyskinetic quadriplegia with cortical blindness and epileptic spasms, West syndrome (but with good outcomes), and hypotonic quadriplegia that later developed into spastic diplegia. Whole-exome sequencing revealed two recurrent GNB1 variants (p.Leu95Pro and p.Ile80Thr) and one novel variant (p.Ser74Leu). A recent investigation revealed large numbers of patients with GNB1 variants. Functional studies of such variants and genotype-phenotype correlation are required to enable future precision medicine.
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http://dx.doi.org/10.1016/j.braindev.2019.10.006DOI Listing
February 2020

Recurrent NUS1 canonical splice donor site mutation in two unrelated individuals with epilepsy, myoclonus, ataxia and scoliosis - a case report.

BMC Neurol 2019 Oct 27;19(1):253. Epub 2019 Oct 27.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama, 236-0004, Japan.

Background: We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis.

Case Presentation: Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson's disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities.

Conclusions: Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.
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http://dx.doi.org/10.1186/s12883-019-1489-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815447PMC
October 2019

A de novo variant in RAC3 causes severe global developmental delay and a middle interhemispheric variant of holoprosencephaly.

J Hum Genet 2019 Nov 16;64(11):1127-1132. Epub 2019 Aug 16.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.
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http://dx.doi.org/10.1038/s10038-019-0656-7DOI Listing
November 2019

Low-prevalence mosaicism of chromosome 18q distal deletion identified by exome-based copy number profiling in a child with cerebral hypomyelination.

Congenit Anom (Kyoto) 2020 May 29;60(3):94-96. Epub 2019 Jul 29.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/cga.12351DOI Listing
May 2020

Pathogenic variants of , , and associated with hypothalamic hamartoma.

Neurology 2019 07 13;93(3):e237-e251. Epub 2019 Jun 13.

From the Departments of Human Genetics (A.F., S. Mitsuhashi, T.M., A.T., S. Miyatake, N. Miyake, N. Matsumoto) and Neurosurgery (M.S.), Yokohama City University Graduate School of Medicine; Departments of Functional Neurosurgery (T.H., H. Shirozu, H.M., M.F., S.K.) and Child Neurology (J.T.), Epilepsy Center, National Hospital Organization Nishiniigata Chuo Hospital Niigata, Japan; Department of Pediatrics and Neurology (M.S.), Wayne State University, Children's Hospital of Michigan, Detroit Medical Center; Department of Pediatrics (M.K.), Showa University School of Medicine, Tokyo; Department of Biochemistry (M.N., H. Saitsu), Hamamatsu University School of Medicine; and Clinical Research Institute (Y.T.), Kanagawa Children's Medical Center, Yokohama, Japan.

Objective: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).

Methods: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.

Results: We identified a germline variant of , which encodes a ciliary protein, and 2 somatic variants of , which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included , which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of ). Furthermore, a combination of a germline and a somatic variant was detected in another patient.

Conclusions: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.
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http://dx.doi.org/10.1212/WNL.0000000000007774DOI Listing
July 2019

A missense variant of SMC1A causes periodic pharmaco-resistant cluster seizures similar to PCDH19-related epilepsy.

Epilepsy Res 2019 09 3;155:106149. Epub 2019 Jun 3.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.

SMC1A variants causing Cornelia de Lange syndrome (CdLS) produce another phenotype characterized by moderate to severe neurological impairment and severe early-onset epilepsy without morphological characteristics of CdLS. The patients are all female and have truncation mutations in SMC1A. The epilepsy also follows a characteristic clinical course with pharmaco-resistant cluster seizures since infancy, mimicking that of PCDH19-related epilepsy. We report here that a missense variant of the SMC1A gene affecting a daughter (proband) and her mother caused similar phenotypes of early-onset (2 years and 1 month of age) and late-onset (12 years of age) epilepsy, respectively. Both patients lacked the morphological characteristics of CdLS, and had severe and moderate intellectual disability, respectively. The cluster seizures were characteristic, occurring approximately every 2-4 weeks (interval; mean ± SD: 20.2 ± 8.3 days) at the peak of the clinical course, especially in the proband. Thus, SMC1A-related encephalopathy is caused not only by truncation mutations but also by missense variants of the SMC1A gene. The periodicity of cluster seizures mimicking that of PCDH19-related epilepsy may characterize SMC1A-related encephalopathy.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.06.001DOI Listing
September 2019

Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation.

Seizure 2019 Oct 29;71:20-23. Epub 2019 May 29.

Department of Pediatrics, Hiroshima University Hospital, Japan.

Purpose: Early myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported.

Methods: We described a female patient with EME due to an SCN1A mutation.

Results: She developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser).

Conclusion: This is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.
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http://dx.doi.org/10.1016/j.seizure.2019.05.024DOI Listing
October 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

A novel de novo frameshift variant in SETD1B causes epilepsy.

J Hum Genet 2019 Aug 20;64(8):821-827. Epub 2019 May 20.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures. This variant is predicted to disrupt a well-conserved carboxyl-terminus SET domain, which is known to modulate gene activities and/or chromatin structure. Previously, two de novo missense mutations in SETD1B were reported in two patients with epilepsy. All three patients including the current patient share similar clinical features. Herein, we report a first epilepsy patient with a frameshift variant in SETD1B, emphasizing a possible pathomechanistic association of SETD1B abnormality with neurodevelopmental delay with epilepsy.
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http://dx.doi.org/10.1038/s10038-019-0617-1DOI Listing
August 2019

Author Correction: A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate.

J Hum Genet 2019 Jul;64(7):701-702

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349-1358, 2016 https://doi.org/10.1038/ng.3676 ). Therefore the mutation is not novel but recurrent. Accordingly, the word "novel" should be deleted throughout the article including the title. Thus, the title should read "A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate."
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http://dx.doi.org/10.1038/s10038-019-0610-8DOI Listing
July 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 Sep;21(9):2160-2161

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019