scholarly journals Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kana Kitayama ◽  
Tomoya Ishiguro ◽  
Masaki Komiyama ◽  
Takayuki Morisaki ◽  
Hiroko Morisaki ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Clinical Information ◽  
Japanese Patients ◽  
Kinase Domain ◽  
Single Family ◽  
Serine Threonine Kinase ◽  
Blood Leukocytes ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
Recurrent Epistaxis

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

scholarly journals Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4014
Author(s):  
Masato Yonamine ◽  
Koichiro Wasano ◽  
Yuichi Aita ◽  
Takehito Sugasawa ◽  
Katsutoshi Takahashi ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Sanger Sequencing ◽  
Clinical Decision Making ◽  
Japanese Patients ◽  
Clinical Decision ◽  
Phenotype Correlation ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
High Incidence

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan

Oncology ◽  
2021 ◽  
Author(s):  
Hiroko Fukushima ◽  
Ryoko Suzuki ◽  
Yuni Yamaki ◽  
Sho Hosaka ◽  
Masako Inaba ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Rare Variants ◽  
Clinical Information ◽  
Japanese Patients ◽  
Pediatric Brain Tumors ◽  
Cancer Predisposition ◽  
Children With Cancer ◽  
White Children ◽  
Pathogenic Variants ◽  
Predisposition Genes

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients’ peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

scholarly journals Genetic variants and clinical phenotypes in Korean patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Author(s):  
Young Jae Lee ◽  
Joo-hyun Jung ◽  
Bo Gyeong Kim ◽  
Mi-Jung Kim ◽  
Eun Hyue Moon ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Screening ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Diagnostic Screening ◽  
Pathogenic Variants ◽  
Recurrent Epistaxis ◽  
Common Clinical Presentation ◽  
History Of ◽  
Standards And Guidelines

Objectives. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasias, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and Endoglin (ENG) are the principal genes whose mutations cause HHT. A multicenter study to investigate the correlation between genetic variations and clinical outcomes in Korean HHT patients has been lacking.Methods. Seventy-two members from 40 families suspected of HHT based on symptoms were genetically screened for pathogenic variants in ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated.Results. In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on ACMG Standards and Guidelines in either ENG or ACVRL1; 26 from 12 families (50%) in ENG, and 16 from 12 families (50%) in ACVRL1. The diagnostic screening of 42 genetically positive HHT patients based on the Cura&#231;ao criteria revealed that 24 patients (57%) were in the definite group, 17 patients (41%) were in the probable group, and 1 patient (2%) was in the unlikely group. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%), and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms.Conclusion. Among patients having ACVRL1 or ENG genetic variants, only about half of them could be clinically diagnosed as definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

scholarly journals Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kei Mizobuchi ◽  
Takaaki Hayashi ◽  
Satoshi Katagiri ◽  
Kazutoshi Yoshitake ◽  
Kaoru Fujinami ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Cone Dystrophy ◽  
Progressive Retinal Atrophy ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
Whole Exome ◽  
Ef Hand ◽  
Genetic Features ◽  
Low Prevalence

AbstractGUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as “pathogenic”, whereas the other five variants, which did not co-segregate with IRDs, were considered “non-pathogenic”. Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

scholarly journals Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 601
Author(s):  
Kyung-Sun Park
Keyword(s):  
General Population ◽  
Pompe Disease ◽  
Genomic Data ◽  
Japanese Patients ◽  
Population Database ◽  
Genome Database ◽  
Genetic Database ◽  
Pathogenic Variants ◽  
Reference Genome Database ◽  
Real Patients

In this study, two different approaches were applied in the analysis of the GAA gene. One was analyzed based on patients with Pompe disease, and the other was analyzed based on GAA genomic data from unaffected carriers in a general population genetic database. For this, GAA variants in Korean and Japanese patients reported in previous studies and in patients reported in the Pompe disease GAA variant database were analyzed as a model. In addition, GAA variants in the Korean Reference Genome Database (KRGDB), the Japanese Multi Omics Reference Panel (jMorp), and the Genome Aggregation Database (gnomAD) were analyzed. Overall, approximately 50% of the pathogenic or likely pathogenic variants (PLPVs) found in unaffected carriers were also found in real patients with Pompe disease (Koreans, 57.1%; Japanese, 46.2%). In addition, there was a moderate positive correlation (Spearman’s correlation coefficient of 0.45–0.69) between the proportion of certain PLPVs in patients and the minor allele frequency of their variants in a general population database. Based on the analysis of general population databases, the total carrier frequency for Pompe disease in Koreans and Japanese was estimated to be 1.7% and 0.7%, respectively, and the predicted genetic prevalence was 1:13,657 and 1:78,013, respectively.

scholarly journals A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
P. Loza ◽  
A. Irmejs ◽  
Z. Daneberga ◽  
E. Miklasevics ◽  
E. Berga-Svitina ◽  
...  
Keyword(s):  
Literature Review ◽  
Local Spectrum ◽  
Single Family ◽  
Baltic Region ◽  
Breast And Ovarian Cancer ◽  
Pathogenic Variants ◽  
Common Founder ◽  
The Baltic ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Several recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region. Methods We present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review. Results Founder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family. Conclusions By combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three “historical” founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

scholarly journals SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1641-1654 ◽  
Author(s):  
Hanna Fares ◽  
Iva Greenwald
Keyword(s):  
Cell Fate ◽  
Point Mutations ◽  
Kinase Domain ◽  
Terminal Region ◽  
Serine Threonine Kinase ◽  
Intracellular Domain ◽  
Cell Fate Decisions ◽  
Threonine Kinase ◽  
Amino Terminal ◽  
Fate Decision

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism

2020 ◽  
Vol 33 (6) ◽  
pp. 691-701 ◽  
Author(s):  
Tatsushi Tanaka ◽  
Kohei Aoyama ◽  
Atsushi Suzuki ◽  
Shinji Saitoh ◽  
Haruo Mizuno
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Japanese Patients ◽  
Thyroid Stimulating Hormone ◽  
Allelic Variant ◽  
Genetic Investigation ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Molecular Genetic Diagnosis

AbstractObjectivesCongenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations.MethodsWe enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH.ResultsWe identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants.ConclusionsThe prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.

scholarly journals Evidence for Selection at thefusedLocus ofDrosophila virilis

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1701-1709 ◽  
Author(s):  
Jorge Vieira ◽  
Brian Charlesworth
Keyword(s):  
Amino Acid ◽  
Aspartic Acid ◽  
Kinase Domain ◽  
Drosophila Virilis ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Usual Equilibrium ◽  
Replacement Site ◽  
Fused Gene ◽  
Significant Linkage

AbstractThe genomic DNA sequence of a 2.4-kb region of the X-linked developmental gene fused was determined in 15 Drosophila virilis strains. One common replacement polymorphism is observed, where a negatively charged aspartic amino acid is replaced by the noncharged amino acid alanine. This replacement variant is located within the serine/threonine kinase domain of the fused gene and is present in ~50% of the sequences in our sample. Significant linkage disequilibrium is detected around this replacement site, although the fused gene is located in a region of the D. virilis X chromosome that seems to experience normal levels of recombination. In a 600-bp region around the replacement site, all eight alanine sequences are identical; of the six aspartic acid sequences, three are also identical. The occurrence of little or no variation within the aspartic acid and alanine haplotypes, coupled with the presence of several differences between them, is very unlikely under the usual equilibrium neutral model. Our results suggest that the fused alanine haplotypes have recently increased in frequency in the D. virilis population.

scholarly journals Clinical Outcome of Mid-Length Proximal Femoral Nail for Patients With Trochanteric Hip Fractures: Preliminary Investigation in a Japanese Cohort of Patients More Than 70 Years Old

2020 ◽  
Vol 11 ◽  
pp. 215145932093644
Author(s):  
Tomohiro Matsumura ◽  
Tsuneari Takahashi ◽  
Mitsuharu Nakashima ◽  
Yoshiya Nibe ◽  
Katsushi Takeshita
Keyword(s):  
Blood Loss ◽  
Internal Fixation ◽  
Clinical Outcomes ◽  
Hip Fractures ◽  
Preliminary Investigation ◽  
Japanese Patients ◽  
Proximal Femoral Nail ◽  
Surgical Time ◽  
Japanese Cohort ◽  
Femoral Nail

Introduction: The TFN-ADVANCED Proximal Femoral Nailing System (TFNA) 235 mm (DePuySynthes) and Proximal Femoral Nail Antirotation (PFNA)-II 240 mm (DePuySynthes) were developed to obtain better stability for patients with trochanteric hip fractures without increasing surgical time and amount of blood loss. However, there are currently no studies concerning clinical and radiological outcomes of patients treated using these proximal femoral nails (PFNs) that have been performed in the Japanese population. The aim of this study was to retrospectively evaluate the clinical outcomes associated with 235 to 240 mm PFNs for Japanese patients >70 years old with trochanteric hip fractures who could walk independently before the injury. Materials and Methods: This study involved a retrospective analysis of data on trochanteric hip fracture patients who had undergone internal fixation from March 2016 to June 2018. The inclusion criteria were patients >70 years old with trochanteric hip fractures who could walk independently before the injury and were followed up for ≥3 months after surgery. Initially, 124 patients were identified, but 33 of these were excluded because other implants were used for internal fixation. Of the remaining 91 patients in whom PFNs were used at the time of internal fixation who were included for the perioperative evaluation, 66 patients followed up for ≥3 months were included in the clinical evaluations. Results: The average surgical time was 56.8 ± 19.6 minutes (range, 23-123 minutes). The average blood loss was 89 ± 41 mL (range, 0-245 mL). The union rate was 98%. Discussion: There were no cases of nail jamming, and all nails were successfully inserted below the end of the distal isthmus without additional reaming to dilate the canal. Conclusions: Proximal femoral nails were a useful implant in Japanese elderly patients with trochanteric hip fractures and gave comparable clinical outcomes despite the femoral length being short and occurrence of intensive bowing.

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