The diphthamide biosynthesis 1 (DPH1) gene encodes one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). ...Diphthamide is the posttranslationally modified histidine residue on EEF2 that promotes protein chain elongation in the ribosome. DPH1 defects result in a failure of protein synthesis involving EEF2, leading to growth defects, embryonic lethality, and cell death. In humans, DPH1 mutations cause developmental delay with a short stature, dysmorphic features, and sparse hair, and are inherited in an autosomal recessive manner (MIM#616901). To date, only two homozygous missense mutations in DPH1 (c.17T>A, p.Met6Lys and c.701T>C, p.Leu234Pro) have been reported. We used WES to identify novel compound heterozygous mutations in DPH1 (c.289delG, p.Glu97Lysfs*8 and c.491T>C, p.Leu164Pro) in a patient from a nonconsanguineous family presenting with intellectual disability, a short stature, craniofacial abnormalities, and external genital abnormalities. The clinical phenotype of all patients with DPH1 mutations, including the current patient, revealed core features, although the external genital anomaly was newly recognized in our case.
Biallelic mutations in the post-GPI attachment to proteins 3 (
) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline ...phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15
mutations have been reported in humans. Here we report a novel homozygous
mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features.
A quantitative assessment was carried out to evaluate the performance of iodine adsorption cartridges attached to gas and powered air-purifying respirators, under radioactive iodine concentrations, ...temperatures, and humidity conditions simulating the post-earthquake conditions at Fukushima Daiichi Nuclear Power Station. The test was conducted at the temperature of 30℃, the radioactive iodine concentration (radioactive methyl iodine concentration) and humidity conditions were varied, radioactive methyl iodine was directly aerated into the adsorption cartridges for a maximum of 10 hours, and the radioactive iodine removal performance of the adsorption cartridges was assessed. Some adsorption cartridges demonstrated a radioactive iodine removal performance of 10 hours or more, while the performance of others decreased with higher relative humidity. Based on the results of these performance assessments, respirator-wearing guidelines at Fukushima Daiichi Nuclear Power Station were established.
Aromatic L-amino acid decarboxylase (AADC) deficiency, caused by a pathogenic variant in the dopa decarboxylase (DDC) gene, is a rare neurometabolic disorder in which catecholamine and serotonin are ...not synthesized. From a large number of reports, it has been recognized that most affected patients show severe developmental delay in a bedridden state and are unable to speak. On the other hand, patients with a mild phenotype with AADC deficiency have been reported, but they number only a few cases. Therefore, the variation of phenotypes of the disease appears to be broad, and it may be challenging to diagnose an atypical phenotype as AADC deficiency.
We report novel compound heterozygous variants in DDC (c.202G > A and c.254C > T) in two sisters, whose main complaint was mild developmental delay, by whole-exome sequencing (WES). Additionally, we describe their clinical features and provide an image that shows the variants located at different sites responsible for the catalysis of AADC in a three-dimensional structure. The patients were prescribed a Monoamine oxidase (MAO) inhibitor after diagnosis.
Our cases indicate that a comprehensive genomic approach helps to diagnose AADC deficiency with atypical features, and underscore the significance of understanding the variations of this disorder for diagnosis and appropriate treatment.
Genetic testing advances have enabled the provision of previously unavailable information on the pathogenicity of genetic variants, frequently necessitating the recontact of former patients by ...clinicians. In Japan, national health insurance coverage was extended to BRCA1/2 testing for the diagnosis of hereditary breast and ovarian cancer for patients who meet certain criteria in 2020, and conditions necessitating recontact were expected to increase. Studies and discussions regarding recontact have been conducted in the U.S. and Europe; however, in Japan, the national discussion around recontact remains undeveloped. We conducted a cross-sectional study by interviewing 73 facilities accredited by the Japanese Organization of Hereditary Breast and Ovarian Cancer regarding the practice of recontacting patients at these facilities. Sixty-six facilities responded that they recontact patients, but only 17 facilities had a protocol for this. The most common reason for recontact was that it could benefit the patient. Facilities that did not recontact stated that they lacked the necessary personnel or services. Most facilities indicated that a recontact system should be implemented in their practice. The increased burden on too few medical personnel, unestablished systems, patient confusion, and the right not to know were cited as barriers to implementing recontact. Although developing recommendations on recontact would be useful for providing equitable healthcare in Japan, there is an urgent need to deepen the discussion on recontacting, as negative opinions about recontacting patients were observed.
Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this ...incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10
) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. ...However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X‐linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch‐based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
Using exome sequencing of 1199 samples including 763 from patients, we identified pathogenic/likely pathogenic copy number variations (CNVs) in 34 (4.5%, 34/763) patients using two CNV‐detection algorithms (eXome Hidden Markov Model XHMM and Nord's method) with the optimization by batch‐ and sex‐based analyses.
Various past, present, and future events are described in text. To understand such text, correct interpretation of temporal information is essential. For this purpose, many corpora associating events ...with temporal information have been constructed. Although these corpora focus on expressions with strong temporality, many expressions have weak temporality, but are still clues to understanding temporal information. In this article, we propose an annotation scheme that comprehensively anchors textual expressions to the time axis. Using this scheme, we annotated 113 documents in the Kyoto University Text Corpus. Because the corpus has already been annotated with predicate-argument structures and coreference relations, it can now be utilized for integrated information analysis of events, entities, and time.
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