Publications by authors named "Tomoko Uehara"

74 Publications

The novel and recurrent variants in exon 31 of CREBBP in Japanese patients with Menke-Hennekam syndrome.

Am J Med Genet A 2021 Oct 15. Epub 2021 Oct 15.

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

Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder caused by the heterozygous variants in exon 30 or 31 of CREBBP (CREB binding protein) gene mapped on 16p13.3. It is characterized by psychomotor delay, variable impairment of intellectual disability (ID), feeding difficulty, autistic behavior, hearing impairment, short stature, microcephaly, and facial dysmorphisms. The CREBBP loss-of-function variants cause Rubinstein-Taybi syndrome-1 (RSTS1). The function of CREBBP leading to MKHK1 has not been clarified so far, and the phenotype of MKHK1 significantly differs from that of RSTS1. We examined six patients with de novo pathogenic variants affecting the last exon of CREBBP, and they shared the clinical features of MKHK1. This study revealed that one frameshift and three nonsense variants of CREBBP cause MKHK1, and inferred that the nonsense variants of the last exon could further help in the elucidation of the etiology of MKHK1.
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http://dx.doi.org/10.1002/ajmg.a.62533DOI Listing
October 2021

BCS1L mutations produce Fanconi syndrome with developmental disability.

J Hum Genet 2021 Oct 15. Epub 2021 Oct 15.

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

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.
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http://dx.doi.org/10.1038/s10038-021-00984-0DOI Listing
October 2021

A patient with compound heterozygosity of SMPD4: Another example of utility of exome-based copy number analysis in autosomal recessive disorders.

Am J Med Genet A 2021 Oct 7. Epub 2021 Oct 7.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

For the efficient diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using exome analysis is required. Recently, our group reported the usefulness of a program called EXCAVATOR2, which screens for CNVs from aligned exome data in bam format. This method is expected to contribute to the identification of structural variants and to improve the diagnosis rate, especially for the diagnosis of autosomal recessive disease, when a conventional exome analysis identifies a pathogenic variant in one allele but not the other. Here we report a 2-year-old Japanese boy with an undiagnosed disease. He had severe neonatal asphyxia, severe intellectual disability, intractable seizures, cerebellar and brainstem hypoplasia and dysmorphic features including a prominent supraorbital ridge, thin upper lip, and prominent antihelix. An exome analysis reinforced with a copy number analysis using the EXCAVATOR2 method revealed that the patient had a hemizygous variant in chr2(GRCh37):g.130925108G>A, NM_017951.4 c.832C>T, p.(Arg278*) in SMPD4 that was derived from his father and a deletion of SMPD4 derived from his mother. The presence of the deletion spanning SMPD4 was confirmed by short-read and long-read whole-genome sequencing. The successful diagnosis of this reported patient demonstrates the diagnostic utility of EXCAVATOR2 and overcomes the weakness of exome analysis for the detection of autosomal recessive diseases in nonconsanguineous families, significantly impacting genetic counseling for family planning.
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http://dx.doi.org/10.1002/ajmg.a.62535DOI Listing
October 2021

Noonan syndrome-like phenotype in a patient with heterozygous ERF truncating variant.

Congenit Anom (Kyoto) 2021 Nov 11;61(6):226-230. Epub 2021 Jul 11.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Craniosynostosis is caused by abnormalities of multiple signaling pathways, including excessive RAS signaling. Recently, a truncating variant in ETS2 repressor factor (ERF), a negative transcriptional regulator of the RAS pathway, was shown to be associated with craniosynostosis. Here, we report a 10-year-old male patient with a heterozygous nonsense mutation, p.Arg183*, in ERF who exhibited craniosynostosis with Noonan syndrome-like phenotypes. In consideration that loss-of-function variants in ERF would result in excessive RAS signaling and RASopathy phenotypes, we propose that ERF may represent a causative gene for Noonan syndrome. Since preceding studies on ERF mutations dealt with patients who were ascertained because of craniosynostosis, further studies are needed to evaluate whether patients with variants in ERF can present with Noonan syndrome-like features without craniosynostosis.
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http://dx.doi.org/10.1111/cga.12435DOI Listing
November 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213725PMC
June 2021

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

Am J Med Genet A 2021 10 29;185(10):2913-2921. 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
October 2021

Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles.

Am J Med Genet A 2021 07 11;185(7):2084-2093. Epub 2021 May 11.

Advanced Insect Research Promotion Center, Kyoto Institute of Technology, Kyoto, Japan.

Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA-related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA-related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6-year-old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14-month-old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild-type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia-deficient zebrafish embryos showed defects of midline-crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild-type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss-of-function mutation.
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http://dx.doi.org/10.1002/ajmg.a.62226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251549PMC
July 2021

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Am J Hum Genet 2021 05;108(5):857-873

GeneDx, Gaithersburg, MD 20877, USA.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206167PMC
May 2021

Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities.

Genet Med 2021 07 6;23(7):1234-1245. Epub 2021 Apr 6.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24.

Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease.

Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
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http://dx.doi.org/10.1038/s41436-021-01129-6DOI Listing
July 2021

Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants.

Am J Med Genet A 2021 06 1;185(6):1836-1840. Epub 2021 Mar 1.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing-genes. RNPC3 (RNA-binding domain-containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di-snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non-synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3-related disorders.
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http://dx.doi.org/10.1002/ajmg.a.62152DOI Listing
June 2021

Fork-shaped mandibular incisors as a novel phenotype of LRP5-associated disorder.

Am J Med Genet A 2021 05 22;185(5):1544-1549. Epub 2021 Feb 22.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

The LRP5 gene encodes a Wnt signaling receptor to which Wnt binds directly. In humans, pathogenic monoallelic variants in LRP5 have been associated with increased bone density and exudative vitreoretinopathy. In mice, LRP5 plays a role in tooth development, including periodontal tissue stability and cementum formation. Here, we report a 14-year-old patient with a de novo non-synonymous variant, p.(Val1245Met), in LRP5 who exhibited mildly reduced bone density and mild exudative vitreoretinopathy together with a previously unreported phenotype consisting of dental abnormalities that included fork-like small incisors with short roots and an anterior open bite, molars with a single root, and severe taurodontism. In that exudative vitreoretinopathy has been reported to be associated with heterozygous loss-of-function variants of LRP5 and that our patient reported here with the p.(Val1245Met) variant had mild exudative vitreoretinopathy, the variant can be considered as an incomplete loss-of-function variant. Alternatively, the p.(Val1245Met) variant can be considered as exerting a dominant-negative effect, as no patients with truncating LRP5 variants and exudative vitreoretinopathy have been reported to exhibit dental anomalies. The documentation of dental anomalies in the presently reported patient strongly supports the notion that LRP5 plays a critical role in odontogenesis in humans, similar to its role in mice.
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http://dx.doi.org/10.1002/ajmg.a.62132DOI Listing
May 2021

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

Am J Med Genet A 2021 04 27;185(4):1113-1119. Epub 2021 Jan 27.

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

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

Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants.

Hum Genome Var 2021 Jan 26;8(1). Epub 2021 Jan 26.

Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Most patients with homozygous or compound heterozygous pathogenic ACO2 variants present with muscular hypotonia features, namely, infantile cerebellar-retinal degeneration. Recently, two studies reported rare familial cases of ACO2 variants presenting as complex hereditary spastic paraplegia (HSP) with broad clinical spectra. Here, we report the case of a 20-year-old Japanese woman with complex HSP caused by compound heterozygous ACO2 variants, revealing a new phenotype of episodic visual loss during febrile illness.
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http://dx.doi.org/10.1038/s41439-021-00136-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838304PMC
January 2021

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.

Genet Med 2021 06 25;23(6):1050-1057. Epub 2021 Jan 25.

Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Purpose: To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19.

Methods: Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19 and CDK19.

Results: We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%).

Conclusion: CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.
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http://dx.doi.org/10.1038/s41436-020-01091-9DOI Listing
June 2021

Pneumococcal Serotype-specific Opsonophagocytic Activity in Interleukin-1 Receptor-associated Kinase 4-deficient Patients.

Pediatr Infect Dis J 2021 05;40(5):460-463

Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Background: The antibody response after pneumococcal vaccines and their effectiveness against invasive pneumococcal disease (IPD) in patients with interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency have not been fully evaluated. Here, we evaluated pneumococcal serotype-specific opsonophagocytic activity (OPA) in IRAK4-deficient patients along with their clinical course.

Methods: We investigated 6 IRAK4-deficient patients in Japan, whose attending physicians could be contacted. We performed OPA measurements using stored and more recent serum samples obtained from these patients.

Results: All patients had received pneumococcal vaccination. Among the 3 patients who had IPD, 2 had an episode of pneumococcal meningitis and the other developed pneumococcal bacteremia 3 years after the occurrence of pneumococcal meningitis. Only one episode of invasive bacterial infection was caused by a Streptococcus pneumoniae vaccine-type strain. An increased opsonization index was found in the sera after vaccination for all IRAK-deficient patients, including when the 23-valent pneumococcal polysaccharide vaccine was used.

Conclusions: A significant increase in levels of OPA against most of the pneumococcal vaccine antigens was observed for all IRAK4-deficient patients. However, IPD could not be prevented by pneumococcal vaccination alone. Therefore, adequate prophylaxis should be provided with antibiotics at least until 8 years of age, along with regular immunoglobulin therapy, particularly during the infantile period.
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http://dx.doi.org/10.1097/INF.0000000000003060DOI Listing
May 2021

Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures.

Am J Med Genet A 2021 04 31;185(4):1182-1186. Epub 2020 Dec 31.

Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan.

The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.
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http://dx.doi.org/10.1002/ajmg.a.62054DOI Listing
April 2021

Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.

Am J Med Genet A 2021 03 27;185(3):884-888. Epub 2020 Dec 27.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.
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http://dx.doi.org/10.1002/ajmg.a.62020DOI Listing
March 2021

GNAO1 mutation-related severe involuntary movements treated with gabapentin.

Brain Dev 2021 Apr 23;43(4):576-579. Epub 2020 Dec 23.

Department of Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Background: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators.

Case: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely.

Conclusion: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.
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http://dx.doi.org/10.1016/j.braindev.2020.12.002DOI Listing
April 2021

Role of chimeric transcript formation in the pathogenesis of birth defects.

Congenit Anom (Kyoto) 2021 May 24;61(3):76-81. Epub 2020 Nov 24.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA-seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: (a) the first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA-seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436-kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat-Wilson syndrome was made. (b) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA-seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186-kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk-Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA-seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion.
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http://dx.doi.org/10.1111/cga.12400DOI Listing
May 2021

Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.

Sci Rep 2020 10 16;10(1):17575. Epub 2020 Oct 16.

Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.

Cyclin-dependent kinase 8 (CDK8) is a member of the CDK/Cyclin module of the mediator complex. A recent study reported that heterozygous missense CDK8 mutations cause a neurodevelopmental disorder in humans. The mechanistic basis of CDK8-related disorder has yet to be delineated. Here, we report 2 patients with de novo missense mutations within the kinase domain of CDK8 along with the results of in vitro and in vivo functional analyses using a zebrafish model. Patient 1 and Patient 2 had intellectual disabilities and congenital anomalies. Exome analyses showed that patient 1 had a heterozygous de novo missense p.G28A variant in the CDK8 (NM_001260.3) gene and patient 2 had a heterozygous de novo missense p.N156S variant in the CDK8 gene. We assessed the pathogenicity of these two variants using cultured-cells and zebrafish model. An in vitro kinase assay of human CDK8 showed that enzymes with a p.G28A or p.N156S substitution showed decreased kinase activity. An in vivo assays of zebrafish overexpression analyses also showed that the p.G28A and p.N156S alleles were hypomorphic alleles. Importantly, the inhibition of CDK8 kinase activity in zebrafish embryos using a specific chemical inhibitor induced craniofacial and heart defects similar to the patients' phenotype. Taken together, zebrafish studies showed that non-synonymous variants in the kinase domain of CDK8 act as hypomorphic alleles causing human congenital disorder.
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http://dx.doi.org/10.1038/s41598-020-74642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567849PMC
October 2020

Heterozygous nonsense variant of CHD8 in a patient with forme-fruste Marfan syndrome and intellectual disability.

Congenit Anom (Kyoto) 2021 Jan 1;61(1):30-32. Epub 2020 Oct 1.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/cga.12393DOI Listing
January 2021

Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome.

Am J Med Genet A 2020 11 27;182(11):2709-2714. Epub 2020 Aug 27.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

The PUF60 gene encodes a ubiquitously expressed essential splicing factor that is recruited to the U2snRNA complex. The complex binds to the 3' splice site of exons in specific target genes and regulates the inclusion or exclusion of such exons. Recently, pathogenic variants of PUF60 have been shown to cause a relatively specific and potentially recognizable pattern of malformation referred to as Verheij syndrome. Here, we report a 12-year-old female patient with a de novo mutation in PUF60 whose phenotype was representative of the milder end of the phenotypic spectrum of Verheij syndrome; the de novo mutation was a frameshift mutation p.(Ser558Cysfs*21) that resulted in the addition of 21 extra amino acids at the carboxy end of the protein. Among the frequent features of Verheij syndrome, the patient exhibited coloboma, cervical spinal segmentation defects, and borderline intellectual functioning, but lacked cardiac abnormalities, deafness, and urogenital abnormalities. The results of RNA analysis using peripheral blood showed the escape of the mutant allele from nonsense-mediated mRNA decay, possibly accounting for the mild phenotype in the presently reported patient. Based on our clinical observations, we inferred that two embryologic processes, closure of the ocular plate and cervical spinal segmentation, are particularly susceptible to deficient PUF60-mediated splicing regulation, compared with other embryogenetic processes leading to the central nervous system, heart, ear, and kidney.
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http://dx.doi.org/10.1002/ajmg.a.61816DOI Listing
November 2020

A Japanese girl with mild xeroderma pigmentosum group D neurological disease diagnosed using whole-exome sequencing.

Hum Genome Var 2020 7;7:22. Epub 2020 Aug 7.

Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.

We report a Japanese girl with mild xeroderma pigmentosum group D neurological disease. She had short stature, cataracts, intellectual disability, and mild skin symptoms. However, she was not clinically diagnosed. Using whole-exome sequencing, we identified compound heterozygous pathogenic variants in . In the future, the patient may develop skin cancer and her neurological symptoms may progress. Early genetic testing is necessary to clarify the cause of symptoms in undiagnosed patients.
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http://dx.doi.org/10.1038/s41439-020-0109-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414221PMC
August 2020

Parallel detection of single nucleotide variants and copy number variants with exome analysis: Validation in a cohort of 700 undiagnosed patients.

Am J Med Genet A 2020 11 11;182(11):2529-2532. Epub 2020 Aug 11.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Copy number variants (CNVs) are significant causes of rare and undiagnosed diseases. Parallel detection of single nucleotide variants (SNVs) and CNVs with exome analysis, if feasible, would shorten the diagnostic closure in a timely manner. We validated such "parallel" approach through a cohort study of 791 undiagnosed patients. In addition to routine exome analysis, we applied an innovative algorithm EXCAVATOR2 which enhances sensitivity by paradoxically exploiting read depth data that covers nonexonic regions where baits were not originally intended to hybridize. About 48 patients had copy number variations, 42 deletions, and 6 duplications with a resolution of 0.51-14.7 mega base pairs. Importantly from a clinical standpoint, we identified three patients with "dual diagnosis" due to concurrent pathogenic CNV and SNV. We suggest "hitting two birds with one stone" approach to exome data is an efficient strategy in deciphering undiagnosed patients and may well be considered as a first-tier genetic test.
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http://dx.doi.org/10.1002/ajmg.a.61822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689761PMC
November 2020

Diagnostic utility of integrated analysis of exome and transcriptome: Successful diagnosis of Au-Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities.

Mol Genet Genomic Med 2020 09 26;8(9):e1364. Epub 2020 Jun 26.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Background: A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor-acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease-causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented.

Method: We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8 years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears.

Result: A SAVNet analysis showed that a heterozygous intronic variant located at the -10 position of exon 5 of the HNRNPK gene on chromosome 9 created a new splice acceptor sequence "ag" and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu-Leu-Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au-Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability.

Conclusion: The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome-transcriptome analysis in clinical settings.
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http://dx.doi.org/10.1002/mgg3.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503209PMC
September 2020

Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1.

Am J Med Genet A 2020 07 15;182(7):1631-1636. Epub 2020 May 15.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.
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http://dx.doi.org/10.1002/ajmg.a.61598DOI Listing
July 2020

Consecutive medical exome analysis at a tertiary center: Diagnostic and health-economic outcomes.

Am J Med Genet A 2020 07 5;182(7):1601-1607. Epub 2020 May 5.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

The utility of whole exome analysis has been extensively demonstrated in research settings, but its clinical utility as a first-tier genetic test has not been well documented from diagnostic and health economic standpoints in real-life clinical settings. We performed medical exome analyses focusing on a clinically interpretable portion of the genome (4,813 genes) as a first-tier genetic test for 360 consecutive patients visiting a genetics clinic at a tertiary children's hospital in Japan, over a 3-year period. Bioinformatics analyses were conducted using standard software. A molecular diagnosis was made in 171 patients involving a total of 107 causative genes. Among these 107 causative genes, 57 genes were classified as genes with potential organ-specific interventions and management strategies. Clinically relevant results were obtained in 26% of the total cohort and 54% of the patients with a definitive molecular diagnosis. Performing the medical exome analysis at the time of the initial visit to the tertiary center, rather than after visits to pertinent specialists, brain MRI examination, and G-banded chromosome testing, would have reduced the financial cost by 197 euros according to retrospective calculation under multiple assumption. The present study demonstrated a high diagnostic yield (47.5%) for singleton medical exome analysis as a first-tier test in a real-life setting. Medical exome analysis yielded clinically relevant information in a quarter of the total patient cohort. The application of genomic testing during the initial visit to a tertiary medical center could be a rational approach to the diagnosis of patients with suspected genetic disorders.
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http://dx.doi.org/10.1002/ajmg.a.61589DOI Listing
July 2020

Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis.

J Pediatr 2020 06 14;221:251-254. Epub 2020 Apr 14.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan. Electronic address:

We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.
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http://dx.doi.org/10.1016/j.jpeds.2020.01.064DOI Listing
June 2020
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