Publications by authors named "Noriko Miyake"

401 Publications

Treatment with bone maturation and average lifespan of HPP model mice by AAV8-mediated neonatal gene therapy via single muscle injection.

Mol Ther Methods Clin Dev 2021 Sep 12;22:330-337. Epub 2021 Jun 12.

Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Hypophosphatasia (HPP) is an inherited skeletal disease characterized by defective bone and tooth mineralization due to a deficiency in tissue-nonspecific alkaline phosphatase (TNALP). Patients with the severe infantile form of HPP may appear normal at birth, but their prognosis is very poor. To develop a practical gene therapy for HPP, we endeavored to phenotypically correct TNALP knockout ( ) mice through adeno-associated virus type 8 (AAV8) vector-mediated, muscle-directed, TNALP expression. Following treatment of neonatal mice with a single intramuscular injection of ARU-2801 (AAV8-TNALP-D10-vector) at 1.0 × 10 vector genomes/body, high plasma ALP levels (19.38 ± 5.02 U/mL) were detected for up to 18 months, and computed tomography analysis showed mature bone mineralization. Histochemical staining for ALP activity in the knee joint revealed ALP activity on the surface of the endosteal bone of mice. Throughout their lives, the surviving treated mice exhibited normal physical activity and a healthy appearance, whereas untreated controls died within 3 weeks. No ectopic calcification or abnormal calcium metabolism was detected in the treated mice. These findings suggest that ARU-2801-mediated neonatal intramuscular gene therapy is both safe and effective, and that this strategy could be a practical option for treatment of the severe infantile form of HPP.
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http://dx.doi.org/10.1016/j.omtm.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408425PMC
September 2021

Novel variants in aromatic L-amino acid decarboxylase deficiency: Case report of sisters with mild phenotype.

Brain Dev 2021 Sep 1. Epub 2021 Sep 1.

Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency, caused by a pathogenic variant in the dopa decarboxylase (DDC) gene, is a rare neurometabolic disorder in which catecholamine and serotonin are not synthesized. From a large number of reports, it has been recognized that most affected patients show severe developmental delay in a bedridden state and are unable to speak. On the other hand, patients with a mild phenotype with AADC deficiency have been reported, but they number only a few cases. Therefore, the variation of phenotypes of the disease appears to be broad, and it may be challenging to diagnose an atypical phenotype as AADC deficiency.

Case Report: We report novel compound heterozygous variants in DDC (c.202G > A and c.254C > T) in two sisters, whose main complaint was mild developmental delay, by whole-exome sequencing (WES). Additionally, we describe their clinical features and provide an image that shows the variants located at different sites responsible for the catalysis of AADC in a three-dimensional structure. The patients were prescribed a Monoamine oxidase (MAO) inhibitor after diagnosis.

Interpretation: Our cases indicate that a comprehensive genomic approach helps to diagnose AADC deficiency with atypical features, and underscore the significance of understanding the variations of this disorder for diagnosis and appropriate treatment.
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http://dx.doi.org/10.1016/j.braindev.2021.07.002DOI Listing
September 2021

De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality.

Hum Mol Genet 2021 Aug 4. Epub 2021 Aug 4.

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

An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy, and brain abnormalities, there were differences in severity, clinical course, and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).
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http://dx.doi.org/10.1093/hmg/ddab224DOI Listing
August 2021

Clinical course of epilepsy and white matter abnormality linked to a novel DYRK1A variant.

Hum Genome Var 2021 Jul 12;8(1):26. Epub 2021 Jul 12.

Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.

Epilepsy and white matter abnormality have been reported in DYRK1A-related intellectual disability syndrome; however, the clinical course has yet to be elucidated. Here, we report the clinical course of an 18-year-old male with a novel heterozygous DYRK1A variant (NM_001396.4: c.957C>G, p.Tyr319*); based on previous reports, epilepsy with this syndrome tends to be well controlled. Follow-up MRIs of the patient's lesion revealed slightly reduced signal intensity compared to the first image.
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http://dx.doi.org/10.1038/s41439-021-00157-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275604PMC
July 2021

Recurrent missense variants in can cause syndromic intellectual disability.

J Med Genet 2021 Jun 28. Epub 2021 Jun 28.

Department of Translational Medicine, Section of Pediatrics, Federico II University Hospital, Naples, Italy.

Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A missense variant in was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm as a neurodevelopmental disease gene, and elucidate the -associated neurodevelopmental phenotype in a patient cohort.

Methods: We discovered a variant in the index case via exome sequencing and sought individuals with variants via international data-sharing initiatives. modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.

Results: We identified 12 unrelated individuals with five missense variants in , four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.

Conclusion: Missense variants in cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.
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http://dx.doi.org/10.1136/jmedgenet-2020-107462DOI Listing
June 2021

De novo pathogenic DHX30 variants in two cases.

Clin Genet 2021 Sep 28;100(3):350-351. Epub 2021 Jun 28.

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

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http://dx.doi.org/10.1111/cge.14013DOI Listing
September 2021

Remitting and exacerbating white matter lesions in leukoencephalopathy with thalamus and brainstem involvement and high lactate.

Brain Dev 2021 Aug 4;43(7):798-803. Epub 2021 May 4.

Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a hereditary disorder caused by biallelic variants in the EARS2 gene. Patients exhibit developmental delay, hypotonia, and hyperreflexia. Brain magnetic resonance imaging (MRI) reveals T2-hyperintensities in the deep white matter, thalamus, and brainstem, which generally stabilize over time. Herein, we report a case of LTBL, showing remitting and exacerbating white matter lesions.

Case Description: A non-consanguineous Japanese boy exhibited unsteady head control with prominent hypotonia, with no family history of neurological diseases. Brain MRI at one year of age revealed extensive T2-hyperintensities on the cerebral white matter, cerebellum, thalamus, basal ganglia, pons, and medulla oblongata. Magnetic resonance spectroscopy of the lesions showed lactate and myoinositol peaks. Whole-exome sequencing yielded novel compound heterozygous EARS2 variants of c.164G>T, p.Arg55Leu and c.484C>T, p.Arg162Trp. Interestingly, the lesions were reduced at three years of age, and new lesions emerged at eight years of age. At 10 years of age, the lesions were changed in the corpus callosum, deep cerebral white matter, and cerebellum, without physical exacerbation. The lesions improved one year later.

Conclusion: We present the first case with remitting and exacerbating brain lesions in LTBL. EARS2 could relate to selective and specific brain regions and age dependency. Although the exact role of EARS2 remains unknown, the remitting and exacerbating imaging changes may be a clue in elucidating a novel EARS2 function in LTBL.
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http://dx.doi.org/10.1016/j.braindev.2021.03.008DOI Listing
August 2021

COG1-congenital disorders of glycosylation: Milder presentation and review.

Clin Genet 2021 Sep 13;100(3):318-323. Epub 2021 May 13.

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

Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1-COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1-CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.
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http://dx.doi.org/10.1111/cge.13980DOI Listing
September 2021

ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H-ATPases is essential for brain development in humans and mice.

Nat Commun 2021 04 8;12(1):2107. Epub 2021 Apr 8.

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

Vacuolar H-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1) and A512P (Atp6v0a1) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1 mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.
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http://dx.doi.org/10.1038/s41467-021-22389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032687PMC
April 2021

Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling.

Nat Commun 2021 04 6;12(1):2046. Epub 2021 Apr 6.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

Bone formation represents a heritable trait regulated by many signals and complex mechanisms. Its abnormalities manifest themselves in various diseases, including sclerosing bone disorder (SBD). Exploration of genes that cause SBD has significantly improved our understanding of the mechanisms that regulate bone formation. Here, we discover a previously unknown type of SBD in four independent families caused by bi-allelic loss-of-function pathogenic variants in TMEM53, which encodes a nuclear envelope transmembrane protein. Tmem53 mice recapitulate the human skeletal phenotypes. Analyses of the molecular pathophysiology using the primary cells from the Tmem53 mice and the TMEM53 knock-out cell lines indicates that TMEM53 inhibits BMP signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of BMP2-activated Smad proteins. Pathogenic variants in the patients impair the TMEM53-mediated blocking effect, thus leading to overactivated BMP signaling that promotes bone formation and contributes to the SBD phenotype. Our results establish a previously unreported SBD entity (craniotubular dysplasia, Ikegawa type) and contribute to a better understanding of the regulation of BMP signaling and bone formation.
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http://dx.doi.org/10.1038/s41467-021-22340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024261PMC
April 2021

Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment.

Brain 2021 05;144(4):1103-1117

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

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype-phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype-phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.
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http://dx.doi.org/10.1093/brain/awab021DOI Listing
May 2021

De novo ATP1A3 variants cause polymicrogyria.

Sci Adv 2021 Mar 24;7(13). Epub 2021 Mar 24.

Department of Pediatrics, Tottori Prefectural Central Hospital, Tottori 680-0901, Japan.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
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http://dx.doi.org/10.1126/sciadv.abd2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990330PMC
March 2021

Variants Associated With X-Linked Intellectual Disability and Congenital Malformation.

Front Cell Dev Biol 2021 3;9:631428. Epub 2021 Mar 3.

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

Background: X-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic variants, was recently reported as a new XLID with additional congenital anomalies.

Methods: We investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.

Results: A hemizygous missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.

Conclusions: Unlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.
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http://dx.doi.org/10.3389/fcell.2021.631428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965969PMC
March 2021

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

Genet Med 2021 07 5;23(7):1202-1210. Epub 2021 Mar 5.

Genetic Health Queensland c/-Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.

Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID.

Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
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http://dx.doi.org/10.1038/s41436-021-01119-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257478PMC
July 2021

Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics.

Am J Med Genet A 2021 05 1;185(5):1561-1568. Epub 2021 Mar 1.

Faculdade de Medicina, Unidade de Genética, Instituto da Criança, Hospital das Clinicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil.

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.
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http://dx.doi.org/10.1002/ajmg.a.62140DOI Listing
May 2021

Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings.

J Autism Dev Disord 2021 Feb 15. Epub 2021 Feb 15.

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

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.
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http://dx.doi.org/10.1007/s10803-021-04910-3DOI Listing
February 2021

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Sci Adv 2021 Jan 20;7(4). Epub 2021 Jan 20.

Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in , encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.
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http://dx.doi.org/10.1126/sciadv.abe2116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817106PMC
January 2021

A patient with a 6q22.1 deletion and a phenotype of non-progressive early-onset generalized epilepsy with tremor.

Epilepsy Behav Rep 2021 16;15:100405. Epub 2020 Nov 16.

Department of Pediatrics, Tohoku University School of Medicine, Sendai 980-8574, Japan.

We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.
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http://dx.doi.org/10.1016/j.ebr.2020.100405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786037PMC
November 2020

A Brazilian case arising from a homozygous canonical splice site SLC35A3 variant leading to an in-frame deletion.

Clin Genet 2021 04 8;99(4):607-608. Epub 2021 Jan 8.

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

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http://dx.doi.org/10.1111/cge.13909DOI Listing
April 2021

Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis.

J Hum Genet 2021 Jun 6;66(6):607-611. Epub 2021 Jan 6.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by osteosclerosis and platyspondyly. DOS is genetically heterogeneous and causally associated with mutations in three genes, SLC29A3, CSF1R, and TNFRSF11A. TNFRSF11A has been known as the causal gene for osteopetrosis, autosomal recessive 7, and is recently reported to cause DOS in three cases, which show a complex genotype-phenotype relationship. The phenotypic spectrum of TNFRSF11A-associated sclerosing bone dysplasia remains unclear and needs to be characterized further in more cases with molecular genetic diagnosis. Here, we report another TNFRSF11A-associated DOS case with a homozygous missense mutation (p.R129C). The mutation effect is different from the previous three cases, in which truncated or elongated RANK proteins were generated in isoform specific manner, thus enriching our understanding of the genotype-phenotype association in TNFRSF11A-associated sclerosing bone dysplasia. Besides DOS, our case presented with intracranial extramedullary hematopoiesis, which is an extremely rare condition and has not been identified in any other sclerosing bone dysplasias with molecular genetic diagnosis. Our findings provide the fourth case of TNFRSF11A-associated DOS and further expand its phenotypic spectrum.
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http://dx.doi.org/10.1038/s10038-020-00891-wDOI Listing
June 2021

Legg-Calvé-Perthes disease in a patient with Bardet-Biedl syndrome: A case report of a novel mutation.

Clin Case Rep 2020 Dec 21;8(12):3110-3115. Epub 2020 Sep 21.

Department of Orthopaedic Surgery Aichi Children's Health and Medical Center Obu Japan.

This article reports a girl with Bardet-Biedl syndrome (BBS) having a novel causative mutation who developed Legg-Calvé-Perthes disease (LCPD). There exists a possibility that the prognosis of LCPD had been adversely affected by the concomitant BBS.
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http://dx.doi.org/10.1002/ccr3.3357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752338PMC
December 2020

Digenic mutations in and impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Rs671 in the aldehyde dehydrogenase 2 gene () is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase ( ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.
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http://dx.doi.org/10.1126/sciadv.abd7197DOI Listing
December 2020

Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy.

Neurol Genet 2020 Dec 19;6(6):e531. Epub 2020 Nov 19.

Department of Neurology (T.I., T.O., Y. Saitoh, S.O., Y.T.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Human Genetics (K.S., A.F., H.F., N. Miyake, T.M., N. Matsumoto), Yokohama City University Graduate School of Medicine, Kanagawa; Department of Pathology and Laboratory Medicine (T.S., Y. Saito), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (T.Y.), Iida Municipal Hospital, Shinshu University School of Medicine, Nagano; Department of Medicine (Neurology and Rheumatology) (Y.M., Y. Sekijima), Shinshu University School of Medicine, Nagano; and Department of Neurology and Stroke Medicine (H.F.), Yokohama City University, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713717PMC
December 2020

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

Parotitis caused by Mycobacteroides abscessus subspecies abscessus.

Auris Nasus Larynx 2020 Nov 24. Epub 2020 Nov 24.

Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Rapidly growing mycobacteria rarely causes parotitis. We report a rare case of Mycobacteroides abscessus subspecies abscessus (MAB) parotitis in a previously healthy 26-year-old woman. She presented to the previous hospital with a swelling over the right parotid region, and a computed tomography scan revealed multiple abscesses in the swollen parotid gland. Histopathology showed granulomatous inflammation with acid-fast bacilli; however, a subsequent culture failed to isolate mycobacterium. Despite repeated antibiotic therapy and multiple surgical interventions including partial incision and drainage of the abscesses, the parotitis did not resolved. At six months after presentation, she was referred to our institute. We performed enlarged resection of the necrotic tissue and abscesses, and the sample cultivated after homogenization was positive for mycobacterium. The isolate was finally identified as MAB. She underwent long-term postoperative antibiotic therapy for MAB, with a favorable outcome. To the best of our knowledge, this is the first case of MAB parotitis where the subspecies has been identified. MAB is much more intractable than the other subspecies. We highlight the importance of the correct identification of MAB, which leads to the appropriate treatment.
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http://dx.doi.org/10.1016/j.anl.2020.11.005DOI Listing
November 2020

Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing.

Genomics 2021 Jan 4;113(1 Pt 2):1044-1053. Epub 2020 Nov 4.

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

We report monozygotic twin girls with syndromic intellectual disability who underwent exome sequencing but with negative pathogenic variants. To search for variants that are unrecognized by exome sequencing, high-fidelity long-read genome sequencing (HiFi LR-GS) was applied. A 12-kb copy-neutral inversion was precisely identified by HiFi LR-GS after trio-based variant filtering. This inversion directly disrupted two genes, CPNE9 and BRPF1, the latter of which attracted our attention because pathogenic BRPF1 variants have been identified in autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP), which later turned out to be clinically found in the twins. Trio-based HiFi LR-GS together with haplotype phasing revealed that the 12-kb inversion occurred de novo on the maternally transmitted chromosome. This study clearly indicates that submicroscopic copy-neutral inversions are important but often uncharacterized culprits in monogenic disorders and that long-read sequencing is highly advantageous for detecting such inversions involved in genetic diseases.
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http://dx.doi.org/10.1016/j.ygeno.2020.10.038DOI Listing
January 2021

Whole exome sequencing of fetal structural anomalies detected by ultrasonography.

J Hum Genet 2021 May 3;66(5):499-507. Epub 2020 Nov 3.

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

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.
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http://dx.doi.org/10.1038/s10038-020-00869-8DOI Listing
May 2021

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 Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.

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 Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 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
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