Publications by authors named "Kumiko Yanagi"

52 Publications

Clinical spectrum of individuals with de novo EBF3 variants or deletions.

Am J Med Genet A 2021 May 29. Epub 2021 May 29.

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

Hypotonia, ataxia and delayed development syndrome (HADDS) (MIM#617330) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in EBF3 (MIM; 607,407), which is located on chromosome 10q26, and was first reported in 2017. To date, missense, nonsense and frameshift variants have been reported as causes of HADDS, and EBF3 pathogenic variants have been predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. It was also reported that total deletion of EBF3 associated with a 10q26.3 microdeletion also causes HADDS symptoms, supporting the concept that HADDS results from haploinsufficiency of EBF3. Here, we report eight unrelated individuals with heterozygous pathogenic variants of EBF3 or haploinsufficiency of EBF3 due to 10q26 deletion, who exhibit clinical findings including craniofacial features of HADDS. In a detailed examination of clinical manifestations in this study, revealed that neurogenic bladder was diagnosed in infancy (the median 6.5 months), was more frequent than previously reported, and required cystostomy in all but one case. For psychomotor delay, it was also found that their motor/skills values were significantly lower than their cognition/adaptation values (p = 0.0016; paired t-test). Therefore, that HADDS is a recognizable syndrome that shares its characteristic facial features, and that neurogenic bladder diagnosed in infancy and psychomotor delay with marked delay in motor/skills are noteworthy findings in the diagnosis and management of individuals with HADDS.
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http://dx.doi.org/10.1002/ajmg.a.62369DOI Listing
May 2021

HECW2-related disorder in four Japanese patients.

Am J Med Genet A 2021 May 28. Epub 2021 May 28.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.

The HECT, C2, and WW domain containing E3 ubiquitin protein ligase 2 gene (HECW2) is involved in protein ubiquitination. Several genes associated with protein ubiquitination have been linked to neurodevelopmental disorders. HECW2-related disorder has been established through the identification of de novo variants in HECW2 in patients with neurodevelopmental disorders with hypotonia, seizures, and absent language. Recently, we identified novel HECW2 variants in four Japanese patients with neurodevelopmental disorders. Regarding motor development, two of the patients cannot walk, whereas the other two can walk with an unsteady gait, owing to hypotonia. All HECW2 variants, including those that were previously reported, are missense, and no loss-of-function variants have been identified. Most of the identified variants are located around the HECT domain. These findings suggest that the dominant negative effects of missense variants around the HECT domain may be the mechanism underlying HECW2-related disorder.
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http://dx.doi.org/10.1002/ajmg.a.62363DOI Listing
May 2021

Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15.

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

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

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.
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http://dx.doi.org/10.1002/ajmg.a.62371DOI Listing
May 2021

Deep intronic deletion in intron 3 of PLP1 is associated with a severe phenotype of Pelizaeus-Merzbacher disease.

Hum Genome Var 2021 Apr 1;8(1):14. Epub 2021 Apr 1.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.

Recently, altered PLP1 splicing was confirmed as a genetic cause of hypomyelination of early myelinating structures (HEMS). A novel deep intronic deletion in intron 3 of PLP1 (NM_000533.5: c.453+59_+259del) was identified, and an in vitro minigene assay detected abnormal splicing patterns. However, the clinical and radiological findings of the patient were compatible with a severe phenotype of Pelizaeus-Merzbacher disease rather than HEMS, which may be due to undetected abnormal PLP1 splicing.
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http://dx.doi.org/10.1038/s41439-021-00144-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016919PMC
April 2021

ETV6-related thrombocytopenia associated with a transient decrease in von Willebrand factor.

Int J Hematol 2021 Mar 25. Epub 2021 Mar 25.

Center for Postgraduate Education and Training, National Center for Child Health and Development (NCCHD), Tokyo, Japan.

ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia, characterized by a bleeding tendency and predisposition to hematological malignancies. The similarity in symptoms makes differentiating immune and congenital thrombocytopenia challenging. We report a 5-year-old girl who presented with chronic thrombocytopenia associated with repetitive and long-lasting epistaxis, leading to blood transfusion for severe anemia. Blood tests showed thrombocytopenia (52 × 10/µL) with normal-sized platelets and transiently low von Willebrand factor (VWF) levels (VWF:RCo 13%, VWF:Ag 50%); therefore, von Willebrand disease type 2 was initially suspected. Repetition of the blood tests revealed normal levels of VWF. Exome and Sanger sequencing identified a germline ETV6 heterozygous variant, c.641C > T:p.(P214L). No additional pathogenic variants were found, including VWF, in the gene panel testing of the 53 known target causative genes for thrombocytopenia. High-throughput exome sequencing for chronic thrombocytopenia can be utilized to differentially diagnose ETV6-related thrombocytopenia from chronic/intractable immune thrombocytopenia and to effectively monitor malignancy.
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http://dx.doi.org/10.1007/s12185-021-03136-4DOI Listing
March 2021

A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1.

J Hum Genet 2021 Mar 15. Epub 2021 Mar 15.

Department of Genome Medicine, National Center for Child Health and Development, Setagaya, Tokyo, Japan.

Auriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.
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http://dx.doi.org/10.1038/s10038-021-00915-zDOI Listing
March 2021

Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing.

Clin Genet 2021 Jul 8;100(1):40-50. Epub 2021 Mar 8.

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

Whole-exome sequencing (WES) enables identification of pathogenic variants, including copy number variants (CNVs). In this study, we performed WES in 101 Japanese patients with unexplained developmental delay (DD) or intellectual disability (ID) (63 males and 38 females), 98 of them with trio-WES. Pathogenic variants were identified in 54 cases (53.5%), including four cases with pathogenic CNVs. In one case, a pathogenic variant was identified by reanalysis of exome data; and in two cases, two molecular diagnoses were identified. Among 58 pathogenic variants, 49 variants occurred de novo in 48 patients, including two somatic variants. The accompanying autism spectrum disorder and external ear anomalies were associated with detection of pathogenic variants with odds ratios of 11.88 (95% confidence interval [CI] 2.52-56.00) and 3.46 (95% CI 1.23-9.73), respectively. These findings revealed the importance of reanalysis of WES data and detection of CNVs and somatic variants in increasing the diagnostic yield for unexplained DD/ID. In addition, genetic testing is recommended when patients suffer from the autism spectrum disorder or external ear anomalies, which potentially suggests the involvement of genetic factors associated with gene expression regulation.
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http://dx.doi.org/10.1111/cge.13951DOI Listing
July 2021

Successful kidney transplantation in a patient with neonatal-onset ILNEB.

Pediatr Transplant 2021 Jan 20:e13971. Epub 2021 Jan 20.

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: ILNEB constitute an autosomal recessive disorder caused by homozygous or compound heterozygous mutation of the gene for the ITGA3. To date, 8 ILNEB patients have been reported, but all 6 neonatal-onset ILNEB patients suffered early death within 2 years. The most common cause of death among previously reported ILNEB patients was exacerbation of the respiratory condition.

Methods: In this study, we describe a case of ILNEB with neonatal onset in a female patient and the genetic and histopathological testing performed.

Results: Our patient had a compound heterozygous mutation in ITGA3. Compared to previously reported patients, this patient exhibited milder clinical and histopathological characteristics. After experiencing a life-threatening respiratory infection at 8 months old, the patient started periodic subcutaneous immunoglobulin treatment once every 1-2 weeks for nephrotic-range proteinuria-induced secondary hypogammaglobulinemia. At the age of 3 years, proteinuria gradually increased with severe edema despite strict internal management. Therefore, our patient underwent unilateral nephrectomy and insertion of a peritoneal dialysis catheter followed by another unilateral nephrectomy. One month later, she underwent an ABO-compatible living-donor kidney transplantation at the age of 4 years.

Conclusions: Our patient is a neonatal-onset ILNEB patient who survived for more than 2 years and underwent successful kidney transplantation.
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http://dx.doi.org/10.1111/petr.13971DOI Listing
January 2021

Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia.

Brain Dev 2021 Apr 13;43(4):566-570. Epub 2021 Jan 13.

Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan.

Background: Rapid-onset dystonia-parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms.

Case Report: We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified.

Discussion: This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.
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http://dx.doi.org/10.1016/j.braindev.2020.12.009DOI Listing
April 2021

X-linked mental retardation and severe short stature with a novel mutation of the gene.

Clin Pediatr Endocrinol 2021 5;30(1):61-64. Epub 2021 Jan 5.

Department of Pediatrics, Oita University Faculty of Medicine, Oita, Japan.

Many monogenetic disorders of short stature have autosomal recessive/dominant form of inheritance. However, X-linked short stature has not been well recognized. Herein, we report a case of a boy from a family with familial severe short stature and mental retardation, who displayed an X-linked recessive trait. The boy at the age of 4 yr and 6 mo presented with remarkable growth failure (height: 76.5 cm [-6.3 SD]) and mental retardation (IQ: 30) and cerebellar volume loss and without an external anomaly or microcephaly to our hospital. A careful interview to determine the family history suggested a genetic background of familial mental retardation and short stature. His mother had mild intellectual disability with normal stature and his maternal uncle had severe mental retardation with remarkably short stature. Whole-exome sequencing identified a pathogenic variant in the gene, NM_004187: exon 23: c.3874_3875del: (p.Ala1292Glnfs*7). He presented with a novel frameshift mutation. His mother was a heterozygous carrier of the variant. This case suggests that a disorder associated with the gene should be considered when patients present with remarkably short stature and X-linked mental retardation.
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http://dx.doi.org/10.1297/cpe.30.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783125PMC
January 2021

A cDNA analysis disclosed the discordance of genotype-phenotype correlation in a patient with attenuated MPS II and a 76-base deletion in the gene for iduronate-2-sulfatase.

Mol Genet Metab Rep 2020 Dec 10;25:100692. Epub 2020 Dec 10.

Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

We previously showed that the genotype-phenotype correlation in MPS II is well-conserved in Japan (Kosuga et al., 2016). Almost all of our patients with attenuated MPS II have missense variants, which is expected to result in residual activity of iduronate-2-sulfatase. In contrast, our patients with severe MPS II have so-called null-type disease-associated variants, such as nonsense variants, frame-shifts, gene insertions, gene deletions and rearrangement with pseudogene (), none of which are expected to result in residual activity. However, we recently encountered a patient with attenuated MPS II who had a presumable null-type disease-associated variant and 76-base deletion located in exon 1 that extended into intron 1. To investigate this discordance, we extracted RNA from the leukocytes of the patient and performed reverse transcription polymerase chain reaction. One of the bands of the cDNA analysis was found to include a nucleotide sequence whose transcript was expected to generate an almost full-length IDS mature peptide lacking only part of its signal peptide as well as only one amino acid at the end of the N-terminus. This suggests that an alternative splicing donor site is generated in exon 1 upstream of the deleted region. Based on these observations, we concluded that the phenotype-genotype discordance in this patient with MPS II was due to the decreased amount of IDS protein induced by the low level of the alternatively spliced mRNA, lacking part of the region coding for the signal peptide but including the region coding almost the full mature IDS protein. The first 25 amino acids at the N-terminus of IDS protein are a signal peptide. The alternative splice transcript has only 13 (1 M-13 L) of those 25 amino acids; 14G-25G are missing, suggesting that the exclusively hydrophobic 1 M-13 L of the signal peptide of IDS might have a crucial role in the signal peptide.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734304PMC
December 2020

Severe gastrointestinal symptoms caused by a novel DDX3X variant.

Eur J Med Genet 2020 Dec 5;63(12):104058. Epub 2020 Sep 5.

Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.

Mutations in DDX3X have recently been identified as a common cause of intellectual disability and congenital anomalies. DDX3X (Xp11.4) encodes the DEAD box RNA helicase that plays an important role in gene regulation, apoptosis, and oncogenesis. Here, we report a case of 6-year-old Japanese girl with a novel variant (NM_001193416.3: c.1574A > G; p.(Tyr525Cys), who exhibited psychomotor retardation, severe constipation, and a recurrent paralytic ileus. This is the second report of severe gastrointestinal symptoms being associated with this disease. This report expands the phenotype caused by DDX3X variants and reveals an important clinical aspect for patients and medical staff.
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http://dx.doi.org/10.1016/j.ejmg.2020.104058DOI Listing
December 2020

A severe case of status dystonicus caused by a de novo KMT2B missense mutation.

Eur J Med Genet 2020 Nov 30;63(11):104057. Epub 2020 Aug 30.

Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan; Genetic Counseling Unit, University of the Ryukyus Hospital, Nishihara, Okinawa, Japan.

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.
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http://dx.doi.org/10.1016/j.ejmg.2020.104057DOI Listing
November 2020

NT5E Genetic Mutation Is a Rare But Important Cause of Intermittent Claudication and Chronic Limb-Threatening Ischemia.

Circ J 2020 06 11;84(7):1183-1188. Epub 2020 Jun 11.

Department of Genome Medicine, National Center for Child Health and Development.

Background: NT5Egenetic mutations are known to result in calcification of joints and arteries (CALJA), and worldwide, 14 patients from 7 families have been reported.Methods and Results:A total of 5 patients from 2 independent families with CALJA were found in Japan. Of them, 3 complained of intermittent claudication (IC), and 1 suffered from bilateral chronic limb-threatening ischemia (CLTI). Whole-exome sequencing analysis revealed an identical mutation pattern (c.G3C on the exon 1 start codon) that was unique compared withNT5Emutations reported in other countries.

Conclusions: Vascular specialists need to recognize CALJA as a rare cause of ischemic IC and CLTI.
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http://dx.doi.org/10.1253/circj.CJ-20-0153DOI Listing
June 2020

A novel homozygous missense mutation in three CACT-deficient patients: clinical and autopsy data.

Hum Genome Var 2020 16;7:11. Epub 2020 Apr 16.

1Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa Japan.

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.
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http://dx.doi.org/10.1038/s41439-020-0098-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162975PMC
April 2020

A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

Mol Genet Genomic Med 2020 03 17;8(3):e1145. Epub 2020 Jan 17.

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

Background: TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain.

Methods: Trio-based whole-exome sequencing was performed on a 7-year-old girl, presenting muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder. Brain magnetic resonance images were normal. She was unable to walk independently and spoke no meaningful words.

Results: We found a de novo variant in TOP2B (NM_001330700.1:c.187C>T, p.(His63Tyr)), which is identical to the previous case. The clinical features of the two individuals with the c.187C>T variant overlapped.

Conclusion: Our study supports the finding that TOP2B variants may cause NDDs.
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http://dx.doi.org/10.1002/mgg3.1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057084PMC
March 2020

Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a family with type 2 collagenopathy.

Am J Med Genet A 2020 03 19;182(3):454-460. Epub 2019 Dec 19.

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

The COL2A1 gene encodes the alpha-1 chain of procollagen type 2. Pathogenic variants in the COL2A1 gene are associated with several different types of skeletal dysplasia collectively known as type 2 collagenopathies. Type 2 collagenopathies have an autosomal dominant inheritance. Some germline or somatogonadal mosaicism cases have been reported. We investigated whether somatogonadal mosaicism occurred in a family with two children suspected of type 2 collagenopathies or related diseases. First, we detected a pathogenic variant in the COL2A1 gene in the two affected children by whole exome sequencing (WES). Next, we performed targeted deep sequencing to their parents without the variant by WES. A low level of COL2A1 mosaicism was revealed in the mother's tissues. We concluded that the mother had somatogonadal mosaicism with the COL2A1 mutation arose in the epiblast, and that the intrafamilial recurrence rate of the disease by the somatogonadal mosaicism was higher than by the germline mosaicism. This report suggests that parental low-level mosaicism should be evaluated in those parents with children carrying de novo germline mutations and the targeted deep sequencing is useful to detect them.
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http://dx.doi.org/10.1002/ajmg.a.61422DOI Listing
March 2020

Exome reports A de novo GNB2 variant associated with global developmental delay, intellectual disability, and dysmorphic features.

Eur J Med Genet 2020 Apr 4;63(4):103804. Epub 2019 Nov 4.

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

Heterotrimeric G proteins are composed of α, β, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gβ proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay.
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http://dx.doi.org/10.1016/j.ejmg.2019.103804DOI Listing
April 2020

Clinical characteristics with long-term follow-up of four Okinawan families with moderate hearing loss caused by an variant.

Hum Genome Var 2019 13;6:37. Epub 2019 Aug 13.

3Department of Otorhinolaryngology-Head and Neck Surgery, University of the Ryukyus, Okinawa, Japan.

We describe the clinical features of four Japanese families with moderate sensorineural hearing loss due to the gene variant. We analyzed 98 hearing loss-related genes in patients with hearing loss originally from the Okinawa Islands using next-generation sequencing. We identified a homozygous variant of the gene encoding otogelin NM_001277269(OTOG): c.330C>G, p.Tyr110* in four families. All patients had moderate hearing loss with a slightly downsloping audiogram, including low frequency hearing loss without equilibrium dysfunction. Progressive hearing loss was not observed over the long-term in any patient. Among the three patients who underwent newborn hearing screening, two patients passed the test. -associated hearing loss was considered to progress early after birth, leading to moderate hearing loss and the later stable phase of hearing loss. Therefore, there are patients whose hearing loss cannot be detected by NHS, making genetic diagnosis of variants highly useful for complementing NHS in the clinical setting. Based on the allele frequency results, hearing loss caused by the p.Tyr110* variant in might be more common than we identified. The p.Tyr110* variant was reported in South Korea, suggesting that this variant is a common cause of moderate hearing loss in Japanese and Korean populations.
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http://dx.doi.org/10.1038/s41439-019-0068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804730PMC
August 2019

Entire FGF12 duplication by complex chromosomal rearrangements associated with West syndrome.

J Hum Genet 2019 Oct 16;64(10):1005-1014. Epub 2019 Jul 16.

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

Complex rearrangements of chromosomes 3 and 9 were found in a patient presenting with severe epilepsy, developmental delay, dysmorphic facial features, and skeletal abnormalities. Molecular cytogenetic analysis revealed 46,XX.ish der(9)(3qter→3q28::9p21.1→9p22.3::9p22.3→9qter)(RP11-368G14+,RP11-299O8-,RP11-905L2++,RP11-775E6++). Her dysmorphic features are consistent with 3q29 microduplication syndrome and inv dup del(9p). Trio-based WES of the patient revealed no pathogenic single nucleotide variants causing epilepsy, but confirmed a 3q28q29 duplication involving FGF12, which encodes fibroblast growth factor 12. FGF12 positively regulates the activity of voltage-gated sodium channels. Recently, only one recurrent gain-of-function variant [NM_021032.4:c.341G>A:p.(Arg114His)] in FGF12 was found in a total of 10 patients with severe early-onset epilepsy. We propose that the patient's entire FGF12 duplication may be analogous to the gain-of-function variant in FGF12 in the epileptic phenotype of this patient.
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http://dx.doi.org/10.1038/s10038-019-0641-1DOI Listing
October 2019

A novel nonsense mutation in a patient with intractable epilepsy and cardiac malformation.

Hum Genome Var 2019 13;6:23. Epub 2019 May 13.

1Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.

Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with -associated CdLS with a novel truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.
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http://dx.doi.org/10.1038/s41439-019-0053-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513828PMC
May 2019

The gene variants in Japanese children with idiopathic pancreatitis.

Hum Genome Var 2019 11;6:17. Epub 2019 Apr 11.

2Department of Genome Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan.

The cystic fibrosis transmembrane conductance regulator () gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of and . The entire gene was sequenced in the patients by combining LA-PCR and next-generation sequencing analysis. To determine a splice-affecting variant, expression was investigated in the nasal epithelial cells by RT-PCR. One (3.6%) and 15 (53.6%) of 28 patients had pathogenic and functionally affected variants in the gene, respectively. Two variants, p.Arg352Gln and p.Arg1453Trp, were found more frequently in the patients compared with one in Japanese healthy controls ( = 0.0078 and 0.044, respectively). We confirmed skipping of exon 10 in the nasal epithelial cells in one patient having a splice-affecting variant (c.1210-12 T(5)) in intron 9. Functionally affected variants of the gene are not so rare in Japanese paediatric patients with idiopathic pancreatitis. Surveying gene variants in a Japanese sample could help identify pancreatitis risk in these children.
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http://dx.doi.org/10.1038/s41439-019-0049-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459923PMC
April 2019

An extremely severe case of Aicardi-Goutières syndrome 7 with a novel variant in IFIH1.

Eur J Med Genet 2020 Feb 6;63(2):103646. Epub 2019 Apr 6.

Division of Neonatology, Center for Maternal-Fetal, Neonatal, and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.

We describe herein an extremely severe case of Aicardi-Goutières syndrome 7 (AGS7). The female patient was the daughter of nonconsanguineous parents and developed cardiomegaly, pericardial effusion, splenomegaly, and intracranial calcification during the fetal period. Because her cardiotocogram showed a non-reassuring fetal status, she was delivered at 29 weeks and 4 days of gestation by an emergency cesarean section. After birth, she suffered from respiratory distress, pulmonary hypertension, refractory fever, recurrent thrombocytopenia, and abdominal distention caused by hepatomegaly and ascites. She showed a lenticulostriate vasculopathy, which was compatible with the fetal intracranial calcification. Despite various intensive care procedures, she died of gradually progressive pulmonary hypertension at 3 months of age. After her death, whole exome sequencing on the patient and the parents was performed and revealed a novel, de novo, heterozygous mutation in the IFIH1 gene (IFIH1:NM_022168:exon12:c.2439A > T:p.Glu813Asp). On the basis of the mutation and the clinical features, the diagnosis was AGS7. Although AGS7 has been regarded as a relatively mild subtype of Aicardi-Goutières syndrome, this case indicates that the c.2439A > T variant of AGS7 can be fatal in early infancy.
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http://dx.doi.org/10.1016/j.ejmg.2019.04.003DOI Listing
February 2020

Recurrent de novo MAPK8IP3 variants cause neurological phenotypes.

Ann Neurol 2019 06 25;85(6):927-933. Epub 2019 Apr 25.

Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.

c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927-933.
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http://dx.doi.org/10.1002/ana.25481DOI Listing
June 2019

A novel mutation in the GATAD2B gene associated with severe intellectual disability.

Brain Dev 2019 Mar 25;41(3):276-279. Epub 2018 Oct 25.

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

Background: The human GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/nucleosome remodeling and deacetylase complex, which is involved in chromatin modification and transcription. Recently, patients with severe intellectual disabilities and characteristic features associated with GATAD2B mutations have been identified.

Case Report: The patient was a 4-year-old male with dysmorphic features, including frontal bossing, hypertelorism, epicanthal folds, down-slanting palpebral fissures, a flat nasal bridge, a high arched palate, and micrognathia. He spoke no meaningful words and exhibited severe intellectual disability. Hypermetropic astigmatism and mild spasticity of the lower extremities were noted. Whole-exome sequencing revealed a de novo missense mutation in GATAD2B (NM_020699:exon4:c.502C>T; p.(Glu168)).

Conclusion: We report a novel GATAD2B mutation in a boy exhibiting bilateral leg spasticity and white matter abnormalities on brain magnetic resonance imaging.
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http://dx.doi.org/10.1016/j.braindev.2018.10.003DOI Listing
March 2019

Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D.

Am J Med Genet A 2018 12 21;176(12):2882-2886. Epub 2018 Nov 21.

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

Cole-Carpenter syndrome is a rare skeletal dysplasia associated with low-bone mass or an osteogenesis imperfecta (OI)-like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15-year-old Japanese boy with short stature of the short-trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole-Carpenter syndrome. He had low-bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2.
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http://dx.doi.org/10.1002/ajmg.a.40643DOI Listing
December 2018

An unclassified variant of activates a cryptic splice site in a patient with CHARGE syndrome.

Hum Genome Var 2018 8;5:18006. Epub 2018 Mar 8.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous mutations. A variant in a splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.
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http://dx.doi.org/10.1038/hgv.2018.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842149PMC
March 2018

Mild prominence of the Sylvian fissure in a Bainbridge-Ropers syndrome patient with a novel frameshift variant in .

Clin Case Rep 2018 02 28;6(2):330-336. Epub 2017 Dec 28.

Okinawa Nanbu Habilitation and Medical Center Naha Japan.

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in gene in addition to typical findings of BRPS.
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http://dx.doi.org/10.1002/ccr3.1361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799615PMC
February 2018

Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene.

Sci Rep 2018 02 2;8(1):2287. Epub 2018 Feb 2.

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

Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450-42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS.
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http://dx.doi.org/10.1038/s41598-018-20691-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797100PMC
February 2018