Publications by authors named "Naomichi Matsumoto"

598 Publications

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder.

Nat Commun 2021 06 18;12(1):3750. Epub 2021 Jun 18.

Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
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http://dx.doi.org/10.1038/s41467-021-23453-wDOI Listing
June 2021

A Japanese adult and two girls with NEDMIAL caused by de novo missense variants in DHX30.

Hum Genome Var 2021 Jun 18;8(1):24. Epub 2021 Jun 18.

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

Lessel et al. reported a novel neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) in 12 individuals and identified six different de novo heterozygous missense variants in DHX30. The other clinical features included muscular hypotonia, feeding difficulties, brain anomalies, autistic features, sleep disturbances, and joint hypermobility. We report a Japanese adult with a novel missense variant and two girls with de novo missense variants in DHX30.
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http://dx.doi.org/10.1038/s41439-021-00155-9DOI Listing
June 2021

A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-weber syndrome.

Hum Mol Genet 2021 Jun 14. Epub 2021 Jun 14.

Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterised by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK-signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harboured a somatic mutation in GNB2 (NM_005273.3:c.232A > G, p.Lys78Glu) which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK-signalling differently, suggesting that dysregulated MAPK-signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of YAP, a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
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http://dx.doi.org/10.1093/hmg/ddab144DOI Listing
June 2021

Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts.

Br J Haematol 2021 Jun 13. Epub 2021 Jun 13.

Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.
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http://dx.doi.org/10.1111/bjh.17569DOI Listing
June 2021

Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.

Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants.

Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins.

Results: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein-protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1.

Conclusion: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41436-021-01222-wDOI Listing
June 2021

Head titubation and irritability as early symptoms of Joubert syndrome with a homozygous NPHP1 variant.

Brain Dev 2021 Jun 2. Epub 2021 Jun 2.

Department of Pediatric Neurology, Miyagi Children's Hospital, Japan.

Background: Joubert syndrome is an autosomal recessive or X-linked genetic disease with a cerebellar vermis defect or hypoplasia, hypotonia, ocular dyskinesia, and mental retardation. In neonates, respiratory problems such as apnea and tachypnea are notable.

Case Report: We report a patient Joubert syndrome with a homozygous NPHP1 variant, who had head titubation with irritability, including exaggerated jitteriness and a marked Morrow reflex appeared soon after birth without neonatal respiratory problems. These symptoms decreased gradually and disappeared until 1 year.

Conclusion: Irritability with head titubation may be an early clinical clue for the clinician to suspect Joubert syndrome.
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http://dx.doi.org/10.1016/j.braindev.2021.04.011DOI Listing
June 2021

Cerebrovascular diseases in two patients with entire NSD1 deletion.

Hum Genome Var 2021 May 24;8(1):20. Epub 2021 May 24.

Department of human genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.

We describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.
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http://dx.doi.org/10.1038/s41439-021-00151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144564PMC
May 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 May 7. Epub 2021 May 7.

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
May 2021

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy.

Hum Genet 2021 Jul 4;140(7):1109-1120. Epub 2021 May 4.

CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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http://dx.doi.org/10.1007/s00439-021-02283-2DOI Listing
July 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 May;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

Pathogenic variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis.

Ann Rheum Dis 2021 Mar 31. Epub 2021 Mar 31.

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

Objectives: To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 ().

Methods: Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1-78.0)). Sanger sequencing of was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively.

Results: was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR.

Conclusions: Genetic screening for pathogenic variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in in the female patient is the first to be reported.
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http://dx.doi.org/10.1136/annrheumdis-2021-220089DOI Listing
March 2021

Phenotypic overlap between pyruvate dehydrogenase complex deficiency and FOXG1 syndrome.

Clin Case Rep 2021 Mar 6;9(3):1711-1715. Epub 2021 Feb 6.

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

Pyruvate dehydrogenase complex (PDHC) deficiency is a mitochondrial disorder. We report two cases of PDHC deficiency with clinical symptoms and brain imaging findings reminiscent of FOXG1 syndrome, suggesting a phenotypic overlap of these disorders.
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http://dx.doi.org/10.1002/ccr3.3883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981633PMC
March 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

Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy.

Front Neurol 2021 26;12:622355. Epub 2021 Feb 26.

Department of Neurology, Toyota Memorial Hospital, Toyota, Japan.

RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.
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http://dx.doi.org/10.3389/fneur.2021.622355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952608PMC
February 2021

Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.

Am J Hum Genet 2021 04 11;108(4):739-748. Epub 2021 Mar 11.

Department of Immunology, Genetics and Pathology, Uppsala University and Science for Life Laboratory, Box 815, 751 08 Uppsala, Sweden. Electronic address:

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059333PMC
April 2021

Preliminary report for Epilepsia Open A case of West syndrome with severe global developmental delay and confirmed KIF5A gene variant.

Epilepsia Open 2021 03 7;6(1):230-234. Epub 2021 Jan 7.

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

Objective: Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome.

Methods: In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay.

Results: Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. I-iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age-matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in , (NM_004984.4:c.710A>T: p. Glu237Val).

Significance: It was concluded that the variant impaired the transport of GABA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy.
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http://dx.doi.org/10.1002/epi4.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918309PMC
March 2021

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

Genet Med 2021 Mar 5. 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
March 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

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Am J Med Genet A 2021 05 24;185(5):1468-1480. 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
May 2021

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

Hum Mol Genet 2021 May;30(9):758-770

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

Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~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-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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161520PMC
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

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

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

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Long-read whole-genome sequencing identified a partial MBD5 deletion in an exome-negative patient with neurodevelopmental disorder.

J Hum Genet 2021 Jan 29. Epub 2021 Jan 29.

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

Whole-exome sequencing (WES) can detect not only single-nucleotide variants in causal genes, but also pathogenic copy-number variations using several methods. However, there may be overlooked pathogenic variations in the out of target genome regions of WES analysis (e.g., promoters), leaving many patients undiagnosed. Whole-genome sequencing (WGS) can potentially analyze such regions. We applied long-read nanopore WGS and our recently developed analysis pipeline "dnarrange" to a patient who was undiagnosed by trio-based WES analysis, and identified a heterozygous 97-kb deletion partially involving 5'-untranslated exons of MBD5, which was outside the WES target regions. The phenotype of the patient, a 32-year-old male, was consistent with haploinsufficiency of MBD5. The transcript level of MBD5 in the patient's lymphoblastoid cells was reduced. We therefore concluded that the partial MBD5 deletion is the culprit for this patient. Furthermore, we found other rare structural variations (SVs) in this patient, i.e., a large inversion and a retrotransposon insertion, which were not seen in 33 controls. Although we considered that they are benign SVs, this finding suggests that our pipeline using long-read WGS is useful for investigating various types of potentially pathogenic SVs. In conclusion, we identified a 97-kb deletion, which causes haploinsufficiency of MBD5 in a patient with neurodevelopmental disorder, demonstrating that long-read WGS is a powerful technique to discover pathogenic SVs.
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http://dx.doi.org/10.1038/s10038-020-00893-8DOI 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