Yongjin Yoo

JAK2 , CALR , and MPL mutation spectrum in Japanese patients with myeloproliferative neoplasms

Recurrent somatic mutations in the JAK2 , MPL , and CALR genes have been described in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These mutations are generally

A study on fiber orientation in the compression molding of fiber reinforced polymer composite material

Abstract It is important to predict the fiber orientation state in controlling the mechanical and physical properties of the final parts in the compression molding process. A computer simulation has been performed to predict the fiber orientation state during compression molding. In the flow analysis, the generalized Hele–Shaw (GHS) model and the control volume finite element method (CVFEM) were employed, and second order tensor representation was used in the fiber orientation analysis. The conventional fiber orientation model has been based on the assumption of homogeneous suspension, i.e. the fiber content is uniform everywhere in the charge. However, in the actual compression molding process where long fibers are used and the fiber content is high, the homogeneous suspension assumption is violated since the fiber separation phenomenon occurs and a fiber concentration gradient is developed. In this study, a new fiber orientation model considering the fiber separation effect is suggested. The results of the analysis are compared with those of experiment and they show good agreement.

Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up

Background Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. Methods We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry (IHC) in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fishers exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome. Results LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+ T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration. Conclusion(s) Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD.BACKGROUND Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. METHODS We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry (IHC) in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fishers exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome. RESULTS LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+ T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration. CONCLUSION(S) Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD.

GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype.

There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile‐onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett‐like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures. One of them had microcephaly, while the other had small head circumference less than 10th centile. There were no abnormal laboratory findings with the exception of a high lactate level. MECP2/CDKL5/FOXG1 genetic tests with an array comparative genomic hybridization revealed no molecular defects. Through whole‐exome sequencing of the proband, we found compound heterozygous ST3GAL5 variants (p.Gly201Arg and p.Cys195Ser), both of which were novel. The siblings were the same compound heterozygotes and their unaffected parents were heterozygous carriers of each variant. Liquid chromatography–mass spectrometry analysis confirmed a low level of GM3 and its downstream metabolites, indicating GM3 synthase deficiency. These cases expanded the clinical and genetic spectrum of the ultra‐rare disease, GM3 synthase deficiency with ST3GAL5 variants.

SATB2-associated syndrome presenting with Rett-like phenotypes.

The SATB2‐associated syndrome (SAS) was proposed recently, after the SATB2 gene was initially discovered to be associated with isolated cleft palate. This syndrome is characterized by intellectual disability with delayed speech development, facial dysmorphism, cleft or high‐arched palate, and dentition problems. Here, we describe two novel SATB2 sequence variants in two unrelated patients presenting with Rett‐like phenotypes. We performed trio‐based whole‐exome sequencing in a 17‐month‐old girl presenting with severe retardation and Rett‐like phenotypes, which revealed a de novo missense variant in SATB2 (p.Glu396Gln). Moreover, targeted sequencing of the SATB2 gene was performed in a 2‐year‐old girl with severe psychomotor retardation, facial hypotonia, and cleft palate who also exhibited some features of Rett syndrome. A nonsense variant in SATB2 was identified in this patient (p.Arg459*). This study expanded the clinical and genetic spectrum of SAS. SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett‐like phenotypes, regardless of the typical features of SAS such as cleft palate.

Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations

Multiple pterygium syndrome (MPS) is an autosomal recessively inherited condition that becomes evident before birth, with pterygium at multiple joints and akinesia. There are two forms of this syndrome that are differentiated by clinical severity: the milder form, Escobar type (OMIM#265000), and the more severe form, lethal type (OMIM#253290). Mutations in CHRNG, which encode the acetylcholine receptor gamma subunit, cause most cases of MPS. Here, we present three patients from two unrelated families showing multiple joint contractures in both the upper and lower limbs. High-arched palates with malocclusion, short neck and micrognathia were observed in all patients. Peripheral blood karyotypes were normal. Whole-exome sequencing analysis of the patients’ genomes led to the discovery of identical missense (p.Pro143Arg) and frameshift deletion variants (p.Pro251fs*45) on CHRNG. These were rare cases of congenital arthrogryposis multiplex related to novel recessive CHRNG variants in two Korean kindred without apparent relatedness.

Wiedemann-Steiner Syndrome With 2 Novel KMT2A Mutations: Variable Severity in Psychomotor Development and Musculoskeletal Manifestation

Wiedemann-Steiner syndrome is a rare genetic disorder characterized by short stature, hairy elbows, facial dysmorphism, and developmental delay. It can also be accompanied by musculoskeletal anomalies such as muscular hypotonia and small hands and feet. Mutations in the KMT2A gene have only recently been identified as the cause of Wiedemann-Steiner syndrome; therefore, only 16 patients from 15 families have been described, and new phenotypic features continue to be added. In this report, we describe 2 newly identified patients with Wiedemann-Steiner syndrome who presented with variable severity. One girl exhibited developmental dysplasia of the hip and fibromatosis colli accompanied by other clinical features, including facial dysmorphism, hypertrichosis, patent ductus arteriosus, growth retardation, and borderline intellectual disability. The other patient, a boy, showed severe developmental retardation with automatic self-mutilation, facial dysmorphism, and hypertrichosis at a later age. Exome sequencing analysis of these patients and their parents revealed a de novo nonsense mutation, p.Gln1978*, of KMT2A in the former, and a missense mutation, p.Gly1168Asp, in the latter, which molecularly confirmed the diagnosis of Wiedemann-Steiner syndrome.

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy

Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.

Reply to “a novel mutation in the transmembrane 6 domain of GABBR2 leads to a rett-like phenotype”

We read the letter by Vuillaume et al with great interest because it provided a beautiful extension of our analyses of GABBR2 de novo missense variants discovered from Rett syndrome and epileptic encephalopathy patients. The discovery and functional analysis of p.Ala707Thr mutation added further evidence to the interesting feature of GABBR2 in determining neurodevelopmental symptoms. This study and the recent array of reports on GABBR2 offer an interesting and important model for elucidating genotypephenotype correlations during brain development. According to the International League Against Epilepsy’s recently revised epilepsy classification, this observation put GABBR2 mutation carriers in a spectrum between “development encephalopathy” and “developmental and epileptic encephalopathy.” Indeed, the pathogenic variants, concerted on the third and sixth transmembrane domains of the G-protein-coupled receptor, altered gammaaminobutyric acid (GABA) signaling, and may determine the clinical output along the spectrum (Fig). Still, several intriguing questions remain. First, how do changes in certain amino acid residues induce variable phenotypic tolerances (Fig)? Are we saturated with identifying additional pathogenic variants of GABBR2? Second, would the signaling intensity be the most important decision maker of clinical symptoms as demonstrated by recent studies, or is it simply a parameter of other fundamental differences during brain development that may give rise to variable symptoms? Third, what are the genetic and functional relationships of GABBR2 with other genes that cause neurodevelopmental disorders when mutated? Finally, would further molecular studies of GABBR2 lead us to understand the pathogenesis mechanism and provide us with a complete picture of drug function on each different variant? Addressing these questions will help us unravel pathogenic mechanisms of pediatric neurological diseases and provide new insights into development and/or repositioning of GABA-modulating agents to benefit such patients.