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3. Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Author

Moreno Traspas, Ricardo, Teoh, Tze Shin, Wong, Pui-Mun, Maier, Michael, Chia, Crystal Y., Lay, Kenneth, Ali, Nur Ain, Larson, Austin, Al Mutairi, Fuad, Al-Sannaa, Nouriya Abbas, Faqeih, Eissa Ali, Alfadhel, Majid, Cheema, Huma Arshad, Dupont, Juliette, Bézieau, Stéphane, Isidor, Bertrand, Low, Dorrain Yanwen, Wang, Yulan, Tan, Grace, Lai, Poh San, Piloquet, Hugues, Joubert, Madeleine, Kayserili, Hulya, Kripps, Kimberly A., Nahas, Shareef A., Wartchow, Eric P., Warren, Mikako, Bhavani, Gandham SriLakshmi, Dasouki, Majed, Sandoval, Renata, Carvalho, Elisa, Ramos, Luiza, Porta, Gilda, Wu, Bin, Lashkari, Harsha Prasada, AlSaleem, Badr, BaAbbad, Raeda M., Abreu Ferrão, Anabela Natália, Karageorgou, Vasiliki, Ordonez-Herrera, Natalia, Khan, Suliman, Bauer, Peter, Cogne, Benjamin, Bertoli-Avella, Aida M., Vincent, Marie, Girisha, Katta Mohan, and Reversade, Bruno

Published
2022
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15. Spinal muscular atrophy carriers with two SMN1 copies

Author

Ar Rochmah, Mawaddah, Awano, Hiroyuki, Awaya, Tomonari, Harahap, Nur Imma Fatimah, Morisada, Naoya, Bouike, Yoshihiro, Saito, Toshio, Kubo, Yuji, Saito, Kayoko, Lai, Poh San, Morioka, Ichiro, Iijima, Kazumoto, Nishio, Hisahide, and Shinohara, Masakazu

Published
2017
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17. NRG1 variant effects in patients with Hirschsprung disease

Author

Gunadi, Nova Yuli Prasetyo Budi, Raman Sethi, Aditya Rifqi Fauzi, Alvin Santoso Kalim, Taufik Indrawan, Kristy Iskandar, Akhmad Makhmudi, Indra Adrianto, and Lai Poh San

Subjects
Hirschsprung disease, Indonesia, NRG1 variant, Transcription factor binding motif, Pediatrics, RJ1-570
Abstract

Abstract Background Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population. Methods We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients. Results All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case–control analysis (p = 0.037). Conclusions This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.

Published
2018
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26. Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients

Author

Yamamoto, Tomoto, Sato, Hideyuki, Lai, Poh San, Nurputra, Dian Kesumapramudya, Harahap, Nur Imma Fatimah, Morikawa, Satoru, Nishimura, Noriyuki, Kurashige, Takashi, Ohshita, Tomohiko, Nakajima, Hideki, Yamada, Hiroyuki, Nishida, Yoshinobu, Toda, Soichiro, Takanashi, Jun-ichi, Takeuchi, Atsuko, Tohyama, Yumi, Kubo, Yuji, Saito, Kayoko, Takeshima, Yasuhiro, Matsuo, Masafumi, and Nishio, Hisahide

Published
2014
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27. Expanding the genetic causes of small‐fiber neuropathy: SCN genes and beyond.

Author

Chan, Amanda C. Y., Kumar, Shivaram, Tan, Grace, Wong, Hiu Yi, Ong, Jonathan J. Y., Chandra, Bharatendu, Huang, Hua, Sharma, Vijay Kumar, and Lai, Poh San

Abstract

Small‐fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ‐fibers and unmyelinated C‐fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A‐gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non‐SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date‐‐‐SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health‐care providers. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Phosphoethanolamine Elevation in Plasma of Spinal Muscular Atrophy Type 1 Patients

Author

Rochmah, Mawaddah Ar, Yogik Onky Silvana Wijaya, Harahap, Nur Imma Fatimah, Tode, Chisato, Takeuchi, Atsuko, Ohuchi, Kazuki, Shimazawa, Masamitsu, Hara, Hideaki, Funato, Michinori, Saito,Toshio, Saito, Kayoko, Lai, Poh San, Awano, Hiroyuki, Shinohara, Masakazu, Nishio, Hisahide, and Niba, Emma Tabe Eko

Published
2020

36. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping

Author

Weale, Mike E., Depondt, Chantal, Macdonald, Stuart J., Smith, Alice, Lai, Poh San, Shorvon, Simon D., Wood, Nicholas W., and Goldstein, David B.

Subjects
Methodology -- Analysis, Genetic research -- Analysis, Genetic research -- Methods, Chromosome mapping -- Genetic aspects, Sodium channels -- Physiological aspects, Neurons -- Genetic aspects, Genomes -- Physiological aspects, Human genetics -- Research, Biological sciences
Published
2003

38. Novel Autoantibodies in Idiopathic Small Fiber Neuropathy.

Author

Chan, Amanda C. Y., Wong, Hiu Yi, Chong, Yao Feng, Lai, Poh San, Teoh, Hock Luen, Ng, Alison Y. Y., Hung, Jennifer H. M., Chan, Yee Cheun, Ng, Kay W. P., Vijayan, Joy, Ong, Jonathan J. Y., Chandra, Bharatendu, Tan, Chi Hsien, Rutt, Nurul H., Tan, Ti Myen, Ismail, Nur Hafiza, Wilder‐Smith, Einar, Schwarz, Herbert, Choi, Hyungwon, and Sharma, Vijay K.

Subjects
AUTOANTIBODIES, NEUROPATHY, PROTEIN folding, STATISTICAL significance, AUTOIMMUNITY
Abstract

Objective: Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state.Methods: Sera from 58 SFN patients and 20 age- and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts.Results: Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). Further subgroup analysis into iSFN and SFN by secondary causes (secondary SFN) in the main cohort showed that MX1 is higher in iSFN compared to secondary SFN (FC = 1.61 vs 0.106, p = 0.009).Interpretation: Novel autoantibodies MX1, DBNL, and KRT8 are found in iSFN. MX1 may allow diagnostic subtyping of iSFN patients. ANN NEUROL 2022;91:66-77. [ABSTRACT FROM AUTHOR]

Published
2022
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39. Mapping Human Genetic Diversity in Asia

Author

Abdulla, Mahmood Ameen, Ahmed, Ikhlak, Assawamakin, Anunchai, Bhak, Jong, Brahmachari, Samir K., Calacal, Gayvelline C., Chaurasia, Amit, Chen, Chien-Hsiun, Chen, Jieming, Chen, Yuan-Tsong, Chu, Jiayou, Cutiongco-de la Paz, Eva Maria C., De Ungria, Maria Corazon A., Delfin, Frederick C., Edo, Juli, Fuchareon, Suthat, Ghang, Ho, Gojobori, Takashi, Han, Junsong, Ho, Sheng-Feng, Hoh, Boon Peng, Huang, Wei, Inoko, Hidetoshi, Jha, Pankaj, Jinam, Timothy A., Jin, Li, Jung, Jongsun, Kangwanpong, Daoroong, Kampuansai, Jatupol, Kennedy, Giulia C., Khurana, Preeti, Kim, Hyung-Lae, Kim, Kwangjoong, Kim, Sangsoo, Kim, Woo-Yeon, Kimm, Kuchan, Kimura, Ryosuke, Koike, Tomohiro, Kulawonganunchai, Supasak, Kumar, Vikrant, Lai, Poh San, Lee, Jong-Young, Lee, Sunghoon, Liu, Edison T., Majumder, Partha P., Mandapati, Kiran Kumar, Marzuki, Sangkot, Mitchell, Wayne, Mukerji, Mitali, Naritomi, Kenji, Ngamphiw, Chumpol, Niikawa, Norio, Nishida, Nao, Oh, Bermseok, Oh, Sangho, Ohashi, Jun, Oka, Akira, Ong, Rick, Padilla, Carmencita D., Palittapongarnpim, Prasit, Perdigon, Henry B., Phipps, Maude Elvira, Png, Eileen, Sakaki, Yoshiyuki, Salvador, Jazelyn M., Sandraling, Yuliana, Scaria, Vinod, Seielstad, Mark, Sidek, Mohd Ros, Sinha, Amit, Srikummool, Metawee, Sudoyo, Herawati, Sugano, Sumio, Suryadi, Helena, Suzuki, Yoshiyuki, Tabbada, Kristina A., Tan, Adrian, Tokunaga, Katsushi, Tongsima, Sissades, Villamor, Lilian P., Wang, Eric, Wang, Ying, Wang, Haifeng, Wu, Jer-Yuarn, Xiao, Huasheng, Xu, Shuhua, Yang, Jin Ok, Shugart, Yin Yao, Yoo, Hyang-Sook, Yuan, Wentao, Zhao, Guoping, and Zilfalil, Bin Alwi

Published
2009
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41. Ethical considerations of preconception and prenatal gene modification in the embryo and fetus.

Author

Mattar, Citra Nurfarah Zaini, Labude, Markus Klaus, Lee, Timothy Nicholas, and Lai, Poh San

Subjects
HUMAN genome, GENOME editing, GENE therapy, FETUS, MEDICAL research, HUMAN experimentation, EMBRYOS, GERM cells, RESEARCH funding
Abstract

The National Academies of Sciences and Medicine 2020 consensus statement advocates the reinstatement of research in preconception heritable human genome editing (HHGE), despite the ethical concerns that have been voiced about interventions in the germline, and outlines criteria for its eventual clinical application to address monogenic disorders. However, the statement does not give adequate consideration to alternative technologies. Importantly, it omits comparison to fetal gene therapy (FGT), which involves gene modification applied prenatally to the developing fetus and which is better researched and less ethically contentious. While both technologies are applicable to the same monogenic diseases causing significant prenatal or early childhood morbidity, the benefits and risks of HHGE are distinct from FGT though there are important overlaps. FGT has the current advantage of a wealth of robust preclinical data, while HHGE is nascent technology and its feasibility for specific diseases still requires scientific proof. The ethical concerns surrounding each are unique and deserving of further discussion, as there are compelling arguments supporting research and eventual clinical translation of both technologies. In this Opinion, we consider HHGE and FGT through technical and ethical lenses, applying common ethical principles to provide a sense of their feasibility and acceptability. Currently, FGT is in a more advanced position for clinical translation and may be less ethically contentious than HHGE, so it deserves to be considered as an alternative therapy in further discussions on HHGE implementation. [ABSTRACT FROM AUTHOR]

Published
2021
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42. Germline genome modification through novel political, ethical, and social lenses.

Author

Xafis, Vicki, Schaefer, G. Owen, Labude, Markus K., Zhu, Yujia, Holm, Soren, Foo, Roger Sik-Yin, Lai, Poh San, and Chadwick, Ruth

Subjects
GENOMES, MEDICAL research, GERM cells, HUMAN genome, SCIENTIFIC community, GENOME editing
Abstract

Much has been written about gene modifying technologies (GMTs), with a particularly strong focus on human germline genome editing (HGGE) sparked by its unprecedented clinical research application in 2018, shocking the scientific community. This paper applies political, ethical, and social lenses to aspects of HGGE to uncover previously underexplored considerations that are important to reflect on in global discussions. By exploring 4 areas—(1) just distribution of HGGE benefits through a realist lens; (2) HGGE through a national interest lens; (3) "broad societal consensus" through a structural injustice lens; and (4) HGGE through a scientific trustworthiness lens—a broader perspective is offered, which ultimately aims to enrich further debates and inform well-considered solutions for developments in this field. The application of these lenses also brings to light the fact that all discussions about scientific developments involve a conscious or unconscious application of a lens that shapes the direction of our thinking. [ABSTRACT FROM AUTHOR]

Published
2021
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43. Dried Blood Spot Screening System for Spinal Muscular Atrophy with Allele-Specific Polymerase Chain Reaction and Melting Peak Analysis.

Author

Wijaya, Yogik Onky Silvana, Nishio, Hisahide, Niba, Emma Tabe Eko, Shiroshita, Tomoyoshi, Kato, Masako, Bouike, Yoshihiro, Tode, Chisato, Ar Rochmah, Mawaddah, Harahap, Nur Imma Fatimah, Nurputra, Dian Kesumapramudya, Okamoto, Kentaro, Saito, Toshio, Takeuchi, Atsuko, Lai, Poh San, Yamaguchi, Seiji, and Shinohara, Masakazu

Published
2021
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47. AB040. Biomarkers for Autism: where are we now and what will the future bring?

Author

Ebstein, Richard P. and Lai, Poh San

Subjects
mental disorders, Part 2: Symposium, behavioral disciplines and activities
Abstract

Autism spectrum disorders (ASD) is a complex disorder in which both genes and environmental factors play important roles. ASD is characterized by a high concordance rate in monozygotic twins pointing to high heritability for this disorder. Notably, the sibling recurrence risk ratio (λs) is 22 for autism. Despite the high heritability clinical symptoms are markedly variable and multiple genetic factors including Mendelian mutations, copy number variations and common polymorphisms all contribute to the genetic load towards passing the clinical threshold to ASD. Indeed, multiple genetic loci have been with various degrees of certainty associated with this disorder. In addition to genetic factors environmental variables and epigenetic signatures are also important modifiers of susceptibility to ASD. For example, studies show that DNA methylation differences can occur in many loci across the genome of ASD subjects. Among biomarkers that have been examined in ASD are metabolic, oxidative stress, mitochondrial dysfunction, methylation, immune dysregulation, amino acids and neuropeptides, peripheral blood gene expression, digit ratio and dysbiosis (gut inflammation) among others. In my talk today after giving an overview (see above) of biomarkers in ASD, I will discuss my own group’s approach that includes both gene markers (serotonin transporter, OXTR and AVPR1a) as well as an innovative endophenotype biomarker approach to better understanding ASD. In a recent study we found that 2D:4D digit ratio (also a proposed marker for ASD) relationship to cognitive empathy (a core deficit in ASD) is dependent in normal subjects on an OXTR SNP linked to ASD in some studies. We have also shown that OXTR and AVPR1a gene polymorphisms are associated in normal subjects with cognitive and emotional empathy respectively. Notably, common polymorphisms in both genes are also associated with ASD. Similarly, the DRD4 gene shows a gender-sensitive association with cognitive empathy. In a parallel talk at this meeting I discuss in some detail how gene expression studies in lymphoblastoid cells may be a marker for ASD as well as personality traits. I will also discuss a finding with a colleague identifying a functional rare variant in autism using genome-wide screen for monoallelic expression. Altogether, our studies have revealed genetic and other biomarkers that jointly contribute to the social cognitive deficits that represent core diagnostic features of ASD. The biomarkers are not specific to ASD but nevertheless shed considerable light on the underlying common polymorphisms and multiple etiologies of this highly heritable disorder characterized by intellectual and social dysfunctions. One promising area of future studies of biomarkers in ASD is prenatal diagnosis using ultrasound.

Published
2015

48. AB038. NGS-based diagnostics for genetic disorders—promises and pitfalls

Author

Lai, Poh-San

Subjects
Part 2: Symposium
Abstract

Genetic testing forms an integral part of clinical management of heritable genetic disorders as it provides options for molecular diagnosis, carrier identification, prenatal diagnosis, etc. The impetus for the development of diagnostic assays for genetic testing of a disease is often influenced by how much is known about its molecular basis, its incidence among the local population and the clinical demand for testing. Subsequent laboratory implementation of a research test for clinical diagnostic testing requires demonstration of clinical utility and validity. Next-generation sequencing (NGS) approaches are increasingly being adopted for clinical diagnostics as the costs becomes increasingly affordable and its utility to resolve diagnostic odysseys has brought resolutions to many families. Validation of such NGS assays is complex but follows similar established guidelines as for traditional genetic tests. There is high analytical sensitivity for most of these assays although the true clinical sensitivity may remain unknown for some disorders. Targeted analysis using NGS is now available for many gene panels, e.g., involving myopathies, cilipathies, cardiomyopathies, etc. as well as for single gene disorders such as Wilson disease, retinoblastoma, RYR1-related diseases, etc. As the costs for sequencing whole exomes and genomes progressively drop further, it is anticipated that these technologies will also begin to transit into the clinical realm. This talk discusses the impact and challenges of NGS in clinical testing and the diagnostic dilemmas in test interpretations for these lab tests.

Published
2015

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