Displaying publications 101 - 120 of 584 in total

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  1. Fulltext The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3
    Chadda KR, Ahmad S, Valli H, den Uijl I, Al-Hadithi AB, Salvage SC, et al.
    Sci Rep, 2017 09 11;7(1):11070.
    PMID: 28894151 DOI: 10.1038/s41598-017-11210-3
    Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p 
    Matched MeSH terms: Phenotype*
  2. Fulltext AMMI and GGE biplot analysis for yield performance and stability assessment of selected Bambara groundnut (Vigna subterranea L. Verdc.) genotypes under the multi-environmental trails (METs)
    Khan MMH, Rafii MY, Ramlee SI, Jusoh M, Al Mamun M
    Sci Rep, 2021 Nov 23;11(1):22791.
    PMID: 34815427 DOI: 10.1038/s41598-021-01411-2
    The stability and high yielding of Vigna subterranea L. Verdc. genotype is an important factor for long-term development and food security. The effects of G × E interaction on yield stability in 30 Bambara groundnut genotypes in four different Malaysian environments were investigated in this research. The experiment used a randomized complete block design with three replications in each environment. Over multiple harvests, yield component traits such as the total number of pods per plant, fresh pods weight (g), hundred seeds weight (g), and yield per hectare were evaluated in the main and off-season in 2020 and 2021. Stability tests for multivariate stability parameters were performed based on analyses of variance. For all the traits, the pooled analysis of variance revealed highly significant (p 
    Matched MeSH terms: Phenotype*
  3. Fulltext Genetic and Global Epigenetic Modification, Which Determines the Phenotype of Transgenic Rice?
    Fan X, Chen J, Wu Y, Teo C, Xu G, Fan X
    Int J Mol Sci, 2020 Mar 06;21(5).
    PMID: 32155767 DOI: 10.3390/ijms21051819
    Transgenic technologies have been applied to a wide range of biological research. However, information on the potential epigenetic effects of transgenic technology is still lacking. Here, we show that the transgenic process can simultaneously induce both genetic and epigenetic changes in rice. We analyzed genetic, epigenetic, and phenotypic changes in plants subjected to tissue culture regeneration, using transgenic lines expressing the same coding sequence from two different promoters in transgenic lines of two rice cultivars: Wuyunjing7 (WYJ7) and Nipponbare (NP). We determined the expression of OsNAR2.1 in two overexpression lines generated from the two cultivars, and in the RNA interference (RNAi) OsNAR2.1 line in NP. DNA methylation analyses were performed on wild-type cultivars (WYJ7 and NP), regenerated lines (CK, T0 plants), segregation-derived wild-type from pOsNAR2.1-OsNAR2.1 (SDWT), pOsNAR2.1-OsNAR2.1, pUbi-OsNAR2.1, and RNAi lines. Interestingly, we observed global methylation decreased in the T0 regenerated line of WYJ7 (CK-WJY7) and pOsNAR2.1-OsNAR2.1 lines but increased in pUbi-OsNAR2.1 and RNAi lines of NP. Furthermore, the methylation pattern in SDWT returned to the WYJ7 level after four generations. Phenotypic changes were detected in all the generated lines except for SDWT. Global methylation was found to decrease by 13% in pOsNAR2.1-OsNAR2.1 with an increase in plant height of 4.69% compared with WYJ7, and increased by 18% in pUbi-OsNAR2.1 with an increase of 17.36% in plant height compared with NP. This suggests an absence of a necessary link between global methylation and the phenotype of transgenic plants with OsNAR2.1 gene over-expression. However, epigenetic changes can influence phenotype during tissue culture, as seen in the massive methylation in CK-WYJ7, T0 regenerated lines, resulting in decreased plant height compared with the wild-type, in the absence of a transformed gene. We conclude that in the transgenic lines the phenotype is mainly determined by the nature and function of the transgene after four generations of transformation, while the global epigenetic modification is dependent on the genetic background. Our research suggests an innovative insight in explaining the reason behind the occurrence of transgenic plants with random and undesirable phenotypes.
    Matched MeSH terms: Phenotype*
  4. Expanding the phenotype of PPP1R21-related neurodevelopmental disorder
    Almannai M, Marafi D, Zaki MS, Maroofian R, Efthymiou S, Saadi NW, et al.
    Clin Genet, 2024 Jun;105(6):620-629.
    PMID: 38356149 DOI: 10.1111/cge.14492
    PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of individuals with available brain imaging include delays in myelination, wavy outline of the bodies of the lateral ventricles, and slight prominence of the bodies of the lateral ventricles. PPP1R21-related neurodevelopmental disorder is associated with a consistent phenotype and should be considered in highly consanguineous individuals presenting with developmental delay/intellectual disability along with coarse facial features.
    Matched MeSH terms: Phenotype*
  5. Secukinumab therapy for paediatric patients with various phenotypes of congenital ichthyosis
    Albela H, Ting IPL, Lee TS, Ooi D, Leong KF
    Clin Exp Dermatol, 2024 Jul 19;49(8):920-922.
    PMID: 38470562 DOI: 10.1093/ced/llae082
    Matched MeSH terms: Phenotype*
  6. RpoS differentially affects the general stress response and biofilm formation in the endophytic Serratia plymuthica G3
    Liu X, Wu Y, Chen Y, Xu F, Halliday N, Gao K, et al.
    Res. Microbiol., 2016 Apr;167(3):168-77.
    PMID: 26671319 DOI: 10.1016/j.resmic.2015.11.003
    The σ(S) subunit RpoS of RNA polymerase functions as a master regulator of the general stress response in Escherichia coli and related bacteria. RpoS has been reported to modulate biocontrol properties in the rhizobacterium Serratia plymuthica IC1270. However, the role of RpoS in the stress response and biofilm formation in S. plymuthica remains largely unknown. Here we studied the role of RpoS from an endophytic S. plymuthica G3 in regulating these phenotypes. Mutational analysis demonstrated that RpoS positively regulates the global stress response to acid or alkaline stresses, oxidative stress, hyperosmolarity, heat shock and carbon starvation, in addition to proteolytic and chitinolytic activities. Interestingly, rpoS mutations resulted in significantly enhanced swimming motility, biofilm formation and production of the plant auxin indole-3-acetic acid (IAA), which may contribute to competitive colonization and environmental fitness for survival. These findings provide further insight into the strain-specific role of RpoS in the endophytic strain G3 of S. plymuthica, where it confers resistance to general stresses encountered within the plant environment. The heterogeneous functionality of RpoS in rhizosphere and endophytic S. plymuthica populations may provide a selective advantage for better adaptation to various physiological and environmental stresses.
    Matched MeSH terms: Phenotype
  7. Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers
    Chua EW, Cree S, Barclay ML, Doudney K, Lehnert K, Aitchison A, et al.
    Pharmacogenomics J, 2015 Oct;15(5):414-21.
    PMID: 25752523 DOI: 10.1038/tpj.2015.9
    Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples and application of genome-wide association studies.
    Matched MeSH terms: Phenotype
  8. Fulltext Successful Pregnancy Outcome in Malaysian Woman with Rare p Phenotype and Anti-PP1P(k) Antibody
    Mohd Azri MS, Kunasegaran K, Azrina A, Siti Nadiah AK
    Indian J Hematol Blood Transfus, 2014 Sep;30(Suppl 1):405-8.
    PMID: 25332632 DOI: 10.1007/s12288-014-0439-4
    We report the first case of young woman with the p phenotype and anti-PP1P(k) antibody in the Malaysian population who was identified during a blood grouping and antibody screening procedure after her first miscarriage. Further family screening detected two other siblings who possessed the same rare phenotype and antibody. Because of difficulties in finding compatible units in the local population, the patient and her two siblings were advised to become regular blood donor. Their blood was frozen for future use. After she had two recurrent miscarriages, her third pregnancy was successfully managed using oral dydrogesterone, which was started from 10 weeks into the pregnancy. Her pregnancy was uneventful and she gave birth to a healthy term neonate.
    Matched MeSH terms: Phenotype
  9. I-int phenotype among three individuals of a Parsi community from Mumbai, India
    Joshi SR
    Immunohematology, 2014;30(1):11-3.
    PMID: 25238244
    The red blood cells (RBCs) of most adult individuals display an I+i- phenotype, whereas those of newborns and some rare adult individuals are typed as I-i+. The phenotype in the latter category, designated as adult i, is under genetic influence as the RBCs of I+i+ individuals display strengths of I and i antigen expression intermediate to that of ordinary adults and ii-adults. As there was no information on the occurrence of adult i phenotype in the Indian population, the present study was undertaken. The RBCs of randomly selected subjects were screened with anti-I and anti-i reagents by a saline tube technique at 220C. Individuals with unusual I and i antigen reactivity patterns were further tested by a semi-quantitative method with a battery of anti-I and anti-i reagents, followed by family studies. Three of the 5864 donors tested showed an elevated strength of i antigen. Further study revealed an intermediate strength of both I and i antigens compared with those on RBCs from adult and cord blood samples. All three probands came from an ethnic Parsi community. The phenotype (referred to as I-int) was shown to be inherited, being passed through two generations, but none of the members of the families had displayed an adult i phenotype. The I-int phenotype detected showed an ethnic association because all three subjects belonged to an endogamous Parsi community that has migrated to India some centuries ago from Persia, the present-day Iran.
    Matched MeSH terms: Phenotype
  10. Fulltext Phenotypic variation in Blastocystis sp. ST3
    Ragavan ND, Govind SK, Chye TT, Mahadeva S
    Parasit Vectors, 2014;7:404.
    PMID: 25174569 DOI: 10.1186/1756-3305-7-404
    Blastocystis, is one of the most common human intestinal protozoan, which has many conflicting reports on its pathogenic role. Gut conditions which obviously varies in asymptomatic individuals, symptomatic and irritable bowel syndrome (IBS) patients in terms of gut flora, pH, osmotic pressure and water potentials could play an important role in its pathogenicity. The present study is the first study to investigate phenotypic characteristics of Blastocystis sp. ST3 isolated from asymptomatic, symptomatic and IBS isolates.
    Matched MeSH terms: Phenotype
  11. Fulltext Haemoglobin Sickle D Punjab: - a case report
    Rahimah A, Syahira Lazira O, Siti Hida HM, Faidatul Syazlin AH, Nur Aisyah A, Nik Hafidzah NM, et al.
    Med J Malaysia, 2014 Feb;69(1):42-3.
    PMID: 24814631 MyJurnal
    Haemoglobin S D-Punjab is a rare compound heterozygous haemoglobinopathy characterised by the presence of two β globin gene variants: Β6(GAG→GTG) and Β121(GAA→CAA). These patients' clinical and haematological features mimic haemoglobin S disease. We describe the first case of doubly heterozygous HbSD-Punjab from Malaysia managed with regular blood transfusion at the age of one. This case highlights the propensity for occurrence of rare phenotypes within our multi-ethnic population and emphasises the importance of accurate genotyping to avoid erroneous counselling, and to plan an effective patient management strategy before complication evolves.
    Matched MeSH terms: Phenotype
  12. Fulltext Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene
    Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, et al.
    Nat Genet, 2013 Oct;45(10):1160-7.
    PMID: 23974870 DOI: 10.1038/ng.2745
    Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
    Matched MeSH terms: Phenotype
  13. Fulltext Morphometric and molecular analysis of mackerel (Rastrelliger spp) from the west coast of Peninsular Malaysia
    Darlina MN, Masazurah AR, Jayasankar P, Jamsari AF, Siti AM
    Genet. Mol. Res., 2011;10(3):2078-92.
    PMID: 21968625 DOI: 10.4238/vol10-3gmr1249
    Mackerel (Scombridae; Rastrelliger) are small commercially important pelagic fish found in tropical regions. They serve as a cheap source of animal protein and are commonly used as live bait. By using a truss morphometrics protocol and RAPD analysis, we examined morphological and genetic variation among 77 individual mackerel that were caught using long lines and gillnets at 11 locations along the west coast of Peninsular Malaysia. Nineteen morphometric traits were evaluated and genetic information was estimated using five 10-base RAPD random primers. Total DNA was extracted from muscle tissue. Morphometric discriminant function analysis revealed that two morphologically distinct groups of Rastrelliger kanagurta and a single group of R. brachysoma can be found along the west coast of Peninsular Malaysia. We also found that the head-related characters and those from the anterior part of the body of Rastrelliger spp significantly contribute to stock assessment of this population. RAPD analysis showed a trend similar to that of the morphometric analysis, suggesting a genetic component to the observed phenotypic differentiation. These data will be useful for developing conservation strategies for these species.
    Matched MeSH terms: Phenotype
  14. "Focal" ventricular tachycardia: insights from catheter ablation
    Mittal S
    Heart Rhythm, 2008 Jun;5(6 Suppl):S64-7.
    PMID: 18456205 DOI: 10.1016/j.hrthm.2008.03.023
    Catheter ablation has come to play an important therapeutic role in the management of some patients with ventricular arrhythmias. An important advance in catheter ablation of ventricular tachycardia (VT) has been the development of three-dimensional catheter-based mapping systems, which permit identification of the tachycardia circuit and facilitate a strategy for catheter ablation. As a result, patients who suffer from "focal" forms of VT have been identified. This can have implications with respect to underlying arrhythmia mechanism, patient prognosis, and therapeutic strategies. The article reviews some insights learned from catheter ablation of focal forms of VT.
    Matched MeSH terms: Phenotype
  15. Phylogeny and phylogeography of Old World fruit bats in the Cynopterus brachyotis complex
    Campbell P, Schneider CJ, Adnan AM, Zubaid A, Kunz TH
    Mol Phylogenet Evol, 2004 Dec;33(3):764-81.
    PMID: 15522802
    Taxonomic relationships within the Old World fruit bat genus, Cynopterus, have been equivocal for the better part of a century. While nomenclature has been revised multiple times on the basis of phenotypic characters, evolutionary relationships among taxa representing the entire geographic range of the genus have not been determined. We used mitochondrial DNA sequence data to infer phylogenetic relationships among the three most broadly distributed members of the genus: C. brachyotis, C. horsfieldi, and C. sphinx, and to assess whether C. brachyotis represents a single widespread species, or a complex of distinct lineages. Results clearly indicate that C. brachyotis is a complex of lineages. C. sphinx and C. horsfieldi haplotypes formed monophyletic groups nested within the C. brachyotis species complex. We identified six divergent mitochondrial lineages that are currently referred to C. brachyotis. Lineages from India, Myanmar, Sulawesi, and the Philippines are geographically well-defined, while in Malaysia two lineages, designated Sunda and Forest, are broadly sympatric and may be ecologically distinct. Demographic analyses of the Sunda and Forest lineages suggest strikingly different population histories, including a recent and rapid range expansion in the Sunda lineage, possibly associated with changes in sea levels during the Pleistocene. The resolution of the taxonomic issues raised in this study awaits combined analysis of morphometric characters and molecular data. However, since both the Indian and Malaysian Forest C. brachyotis lineages are apparently ecologically restricted to increasingly fragmented forest habitat, we suggest that reevaluation of the conservation status of populations in these regions should be an immediate goal.
    Matched MeSH terms: Phenotype
  16. Fulltext Misfolded N-CoR is Linked to the Ectopic Reactivation of CD34/Flt3-Based Stem-Cell Phenotype in Promyelocytic and Monocytic Acute Myeloid Leukemia
    Nin DS, Li F, Visvanathan S, Khan M
    Front Oncol, 2015;5:210.
    PMID: 26500885 DOI: 10.3389/fonc.2015.00210
    Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial for the commitment of primitive hematopoietic cells to cells of myeloid lineage and that misfolded N-CoR may contribute to transformation of committed myeloid cells through the ectopic reactivation of Flt3/CD34-based stem cell phenotypes in promyelocytic and monocytic AML. Moreover, these findings provide novel mechanistic insights into the formation of leukemic stem cells in subsets of AML and identify the misfolded N-CoR as a subtype-specific biomarker of AML.
    Matched MeSH terms: Phenotype
  17. Fulltext Loktanella spp. Gb03 as an algicidal bacterium, isolated from the culture of Dinoflagellate Gambierdiscus belizeanus
    Bloh AH, Usup G, Ahmad A
    Vet World, 2016 Feb;9(2):142-6.
    PMID: 27051199 DOI: 10.14202/vetworld.2016.142-146
    AIM: Bacteria associated with harmful algal blooms can play a crucial role in regulating algal blooms in the environment. This study aimed at isolating and identifying algicidal bacteria in Dinoflagellate culture and to determine the optimum growth requirement of the algicidal bacteria, Loktanella sp. Gb-03.

    MATERIALS AND METHODS: The Dinoflagellate culture used in this study was supplied by Professor Gires Usup's Laboratory, School of Environmental and Natural Resources Sciences, Faculty of Science and Technology, University Kebangsaan Malaysia, Malaysia. The culture was used for the isolation of Loktanella sp., using biochemical tests, API 20 ONE kits. The fatty acid content of the isolates and the algicidal activity were further evaluated, and the phenotype was determined through the phylogenetic tree.

    RESULTS: Gram-negative, non-motile, non-spore-forming, short rod-shaped, aerobic bacteria (Gb01, Gb02, Gb03, Gb04, Gb05, and Gb06) were isolated from the Dinoflagellate culture. The colonies were pink in color, convex with a smooth surface and entire edge. The optimum growth temperature for the Loktanella sp. Gb03 isolate was determined to be 30°C, in 1% of NaCl and pH7. Phylogenetic analysis based on 16S rRNA gene sequences showed that the bacterium belonged to the genus Loktanella of the class Alphaproteobacteria and formed a tight cluster with the type strain of Loktanella pyoseonensis (97.0% sequence similarity).

    CONCLUSION: On the basis of phenotypic, phylogenetic data and genetic distinctiveness, strain Gb-03, were placed in the genus Loktanella as the type strain of species. Moreover, it has algicidal activity against seven toxic Dinoflagellate. The algicidal property of the isolated Loktanella is vital, especially where biological control is needed to mitigate algal bloom or targeted Dinoflagellates.

    Matched MeSH terms: Phenotype
  18. Fulltext The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod
    Patmanathan SN, Yap LF, Murray PG, Paterson IC
    J Cell Mol Med, 2015 Oct;19(10):2329-40.
    PMID: 26171944 DOI: 10.1111/jcmm.12635
    Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.
    Matched MeSH terms: Phenotype
  19. Fulltext Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing
    Drew AP, Zhu D, Kidambi A, Ly C, Tey S, Brewer MH, et al.
    Mol Genet Genomic Med, 2015 Mar;3(2):143-54.
    PMID: 25802885 DOI: 10.1002/mgg3.126
    Inherited peripheral neuropathies (IPNs) are a group of related diseases primarily affecting the peripheral motor and sensory neurons. They include the hereditary sensory neuropathies (HSN), hereditary motor neuropathies (HMN), and Charcot-Marie-Tooth disease (CMT). Using whole-exome sequencing (WES) to achieve a genetic diagnosis is particularly suited to IPNs, where over 80 genes are involved with weak genotype-phenotype correlations beyond the most common genes. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identified 41 missense sequence variants in the known IPN genes in our cohort of 110 index patients. Nine variants (8%), identified in the genes MFN2, GJB1, BSCL2, and SETX, are previously reported mutations and considered to be pathogenic in these families. Twelve novel variants (11%) in the genes NEFL, TRPV4, KIF1B, BICD2, and SETX are implicated in the disease but require further evidence of pathogenicity. The remaining 20 variants were confirmed as polymorphisms (not causing the disease) and are detailed here to help interpret sequence variants identified in other family studies. Validation using segregation, normal controls, and bioinformatics tools was valuable as supporting evidence for sequence variants implicated in disease. In addition, we identified one SETX sequence variant (c.7640T>C), previously reported as a putative mutation, which we have confirmed as a nonpathogenic rare polymorphism. This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well-defined cases remains important and will account for most positive results.
    Matched MeSH terms: Phenotype
  20. A single, large deletion accounts for all the beta-globin gene mutations in twenty families from Sabah (North Borneo), Malaysia. Mutation in brief no. 240. Online
    Thong MK, Rudzki Z, Hall J, Tan JA, Chan LL, Yap SF
    Hum Mutat, 1999;13(5):413.
    PMID: 10338100 DOI: 10.1002/(SICI)1098-1004(1999)13:5<413::AID-HUMU15>
    Beta-thalassemia major is one of the commonest genetic disorders in South-East Asia. The spectrum of beta-thalassemia mutations in the various ethnic sub-populations on the island of Borneo is unknown. We studied 20 Dusun children from the East Malaysian state of Sabah (North Borneo) with a severe beta-thalassemia major phenotype, using a combination of Southern analysis, polymerase chain reaction analysis and direct sequencing. We found the children to be homozygous for a large deletion, which has a 5' breakpoint at position -4279 from the cap site of the beta-globin gene (HBB) with the 3' breakpoint located in a L1 family of repetitive sequences at an unknown distance from the beta-globin gene. This was similar to a recent finding of a large deletion causing beta-thalassemia first described in unrelated beta-thalassemia heterozygotes of Filipino descent. This report describes the first 20 families with homozygosity of the deletion causing a severe phenotype. It provides the first information on the molecular epidemiology of beta-thalassemia in Sabah. This finding has implications for the population genetics and preventative strategies for beta-thalassemia major for nearly 300 million individuals in South-East Asia.
    Matched MeSH terms: Phenotype
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