Displaying publications 1 - 20 of 80 in total

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  1. Wilcox N, Dumont M, González-Neira A, Carvalho S, Joly Beauparlant C, Crotti M, et al.
    Nat Genet, 2023 Sep;55(9):1435-1439.
    PMID: 37592023 DOI: 10.1038/s41588-023-01466-z
    Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P 
    Matched MeSH terms: Mutation, Missense/genetics
  2. Ishak SNH, Kamarudin NHA, Ali MSM, Leow ATC, Rahman RNZRA
    Molecules, 2020 Jul 28;25(15).
    PMID: 32731607 DOI: 10.3390/molecules25153430
    A comparative structure analysis between space- and an Earth-grown T1 recombinant lipase from Geobacillus zalihae had shown changes in the formation of hydrogen bonds and ion-pair interactions. Using the space-grown T1 lipase validated structure having incorporated said interactions, the recombinant T1 lipase was re-engineered to determine the changes brought by these interactions to the structure and stability of lipase. To understand the effects of mutation on T1 recombinant lipase, five mutants were developed from the structure of space-grown T1 lipase and biochemically characterized. The results demonstrate an increase in melting temperature up to 77.4 °C and 76.0 °C in E226D and D43E, respectively. Moreover, the mutated lipases D43E and E226D had additional hydrogen bonds and ion-pair interactions in their structures due to the improvement of stability, as observed in a longer half-life and an increased melting temperature. The biophysical study revealed differences in β-Sheet percentage between less stable (T118N) and other mutants. As a conclusion, the comparative analysis of the tertiary structure and specific residues associated with ion-pair interactions and hydrogen bonds could be significant in revealing the thermostability of an enzyme with industrial importance.
    Matched MeSH terms: Mutation, Missense*
  3. Bukhari N, Leow ATC, Abd Rahman RNZR, Mohd Shariff F
    Molecules, 2020 Jul 28;25(15).
    PMID: 32731608 DOI: 10.3390/molecules25153433
    Rational design is widely employed in protein engineering to tailor wild-type enzymes for industrial applications. The typical target region for mutation is a functional region like the catalytic site to improve stability and activity. However, few have explored the role of other regions which, in principle, have no evident functionality such as the N-terminal region. In this study, stability prediction software was used to identify the critical point in the non-functional N-terminal region of L2 lipase and the effects of the substitution towards temperature stability and activity were determined. The results showed 3 mutant lipases: A8V, A8P and A8E with 29% better thermostability, 4 h increase in half-life and 6.6 °C higher thermal denaturation point, respectively. A8V showed 1.6-fold enhancement in activity compared to wild-type. To conclude, the improvement in temperature stability upon substitution showed that the N-terminal region plays a role in temperature stability and activity of L2 lipase.
    Matched MeSH terms: Mutation, Missense*
  4. Ruszymah BHI, Wahida IF, Zakinah Y, Zahari Z, Norazlinda MD, Saim L, et al.
    Med J Malaysia, 2005 Aug;60(3):269-74.
    PMID: 16379178
    Twenty percent of all childhood deafness is due to mutations in the GJB2 gene (Connexin 26). The aim of our study was to determine the prevalence and spectrum of GJB2 mutations in childhood deafness in Malaysia. We analyzed the GJB2 gene in 51 deaf students from Sekolah Pendidikan Khas Alor Setar, Kedah. Bidirectional sequencing indicates that 25% of our childhood deafness has mutation in their GJB2 gene. Sixty two percent of these children demonstrate V37I missense mutation. Interestingly, V37I mutation in the GJB2 gene have been reported as polymorphism in Western countries, however in our country it behaved as a potentially disease-causing missense mutation, causing childhood deafness as it was not found in the normal control.
    Matched MeSH terms: Mutation, Missense*
  5. Beaman GM, Galatà G, Teik KW, Urquhart JE, Aishah A, O'Sullivan J, et al.
    Clin Genet, 2019 12;96(6):515-520.
    PMID: 31441039 DOI: 10.1111/cge.13631
    CHRM3 codes for the M3 muscarinic acetylcholine receptor that is located on the surface of smooth muscle cells of the detrusor, the muscle that effects urinary voiding. Previously, we reported brothers in a family affected by a congenital prune belly-like syndrome with mydriasis due to homozygous CHRM3 frameshift variants. In this study, we describe two sisters with bladders that failed to empty completely and pupils that failed to constrict fully in response to light, who are homozygous for the missense CHRM3 variant c.352G > A; p.(Gly118Arg). Samples were not available for genotyping from their brother, who had a history of multiple urinary tract infections and underwent surgical bladder draining in the first year of life. He died at the age of 6 years. This is the first independent report of biallelic variants in CHRM3 in a family with a rare serious bladder disorder associated with mydriasis and provides important evidence of this association.
    Matched MeSH terms: Mutation, Missense/genetics*
  6. Ali EZ, Zakaria Y, Mohd Radzi MA, Ngu LH, Jusoh SA
    Biomed Res Int, 2018;2018:4320831.
    PMID: 30175132 DOI: 10.1155/2018/4320831
    Ornithine transcarbamylase deficiency (OTCD), an X-linked disorder that results from mutations in the OTC gene, causes hyperammonemia and leads to various clinical manifestations. Mutations occurring close to the catalytic site of OTCase can cause severe OTCD phenotypes compared with those caused by mutations occurring on the surface of this protein. In this study, we report two novel OTC missense mutations, Q171H and N199H, found in Malaysian patients. Q171H and N199H caused neonatal onset OTCD in a male and late OTCD in a female, respectively. In silico predictions and molecular docking were performed to examine the effect of these novel mutations, and the results were compared with other 30 known OTC mutations. In silico servers predicted that Q171H and N199H, as well as 30 known missense mutations, led to the development of OTCD. Docking analysis indicated that N-(phosphonoacetyl)-L-ornithine (PALO) was bound to the catalytic site of OTCase mutant structure with minimal conformational changes. However, the mutations disrupted interatomic interactions in the catalytic site. Therefore, depending on the severity of disruption occurring at the catalytic site, the mutation may affect the efficiency of mechanism and functions of OTCase.
    Matched MeSH terms: Mutation, Missense*
  7. Shepherdson JL, Hutchison K, Don DW, McGillivray G, Choi TI, Allan CA, et al.
    Am J Hum Genet, 2024 Mar 07;111(3):487-508.
    PMID: 38325380 DOI: 10.1016/j.ajhg.2024.01.007
    Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
    Matched MeSH terms: Mutation, Missense/genetics
  8. Helmi MAM, Hussain S
    J ASEAN Fed Endocr Soc, 2020;35(1):125-128.
    PMID: 33442181 DOI: 10.15605/jafes.035.01.22
    Developmental delay, Epilepsy and Neonatal Diabetes (DEND) syndrome is the most severe form of Permanent Neonatal Diabetes with KCNJ11 gene mutation which accounts for most of the cases. We report the first DEND syndrome in Malaysia with heterozygous missense mutation Q52R at KCNJ11 (Kir6.2) gene with delayed presentation beyond 6 months of age and failure to transition to glibenclamide. This report signifies the phenotypical variability among patients with the same genetic mutation and the different response to treatment.
    Matched MeSH terms: Mutation, Missense
  9. Balasubramaniam S, Choy YS, Talib A, Norsiah MD, van den Heuvel LP, Rodenburg RJ
    JIMD Rep, 2012;5:113-22.
    PMID: 23430926 DOI: 10.1007/8904_2011_107
    Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases caused by defects in the oxidative phosphorylation (OXPHOS) system. Given the complexity and intricacy of the OXPHOS system, it is not surprising that the underlying molecular defect remains unidentified in many patients with a mitochondrial disorder. Here, we report the clinical features and diagnostic workup leading to the elucidation of the genetic basis for a combined complex I and IV OXPHOS deficiency secondary to a mitochondrial translational defect in an infant who presented with rapidly progressive liver failure, encephalomyopathy, and severe refractory lactic acidemia. Sequencing of the GFM1 gene revealed two inherited novel, heterozygous mutations: a.539delG (p.Gly180AlafsX11) in exon 4 which resulted in a frameshift mutation, and a second c.688G > A (p.Gly230Ser) mutation in exon 5. This missense mutation is likely to be pathogenic since it affects an amino acid residue that is highly conserved across species and is absent from the dbSNP and 1,000 genomes databases. Review of literature and comparison were made with previously reported cases of this recently identified mitochondrial disorder encoded by a nuclear gene. Although limited in number, nuclear gene defects causing mitochondrial translation abnormalities represent a new, rapidly expanding field of mitochondrial medicine and should potentially be considered in the diagnostic investigation of infants with progressive hepatoencephalomyopathy and combined OXPHOS disorders.
    Matched MeSH terms: Mutation, Missense
  10. Tan CS, Hassan M, Mohamed Hussein ZA, Ismail I, Ho KL, Ng CL, et al.
    Plant Physiol Biochem, 2018 Feb;123:359-368.
    PMID: 29304481 DOI: 10.1016/j.plaphy.2017.12.033
    Geraniol degradation pathway has long been elucidated in microorganisms through bioconversion studies, yet weakly characterised in plants; enzyme with specific nerol-oxidising activity has not been reported. A novel cDNA encodes nerol dehydrogenase (PmNeDH) was isolated from Persicaria minor. The recombinant PmNeDH (rPmNeDH) is a homodimeric enzyme that belongs to MDR (medium-chain dehydrogenases/reductases) superfamily that catalyses the first oxidative step of geraniol degradation pathway in citral biosynthesis. Kinetic analysis revealed that rPmNeDH has a high specificity for allylic primary alcohols with backbone ≤10 carbons. rPmNeDH has ∼3 fold higher affinity towards nerol (cis-3,7-dimethyl-2,6-octadien-1-ol) than its trans-isomer, geraniol. To our knowledge, this is the first alcohol dehydrogenase with higher preference towards nerol, suggesting that nerol can be effective substrate for citral biosynthesis in P. minor. The rPmNeDH crystal structure (1.54 Å) showed high similarity with enzyme structures from MDR superfamily. Structure guided mutation was conducted to describe the relationships between substrate specificity and residue substitutions in the active site. Kinetics analyses of wild-type rPmNeDH and several active site mutants demonstrated that the substrate specificity of rPmNeDH can be altered by changing any selected active site residues (Asp280, Leu294 and Ala303). Interestingly, the L294F, A303F and A303G mutants were able to revamp the substrate preference towards geraniol. Furthermore, mutant that exhibited a broader substrate range was also obtained. This study demonstrates that P. minor may have evolved to contain enzyme that optimally recognise cis-configured nerol as substrate. rPmNeDH structure provides new insights into the substrate specificity and active site plasticity in MDR superfamily.
    Matched MeSH terms: Mutation, Missense
  11. Tang MM, Surana U, Leong KF, Pramano ZAD
    Int J Dermatol, 2021 Jul;60(7):e288-e290.
    PMID: 33728648 DOI: 10.1111/ijd.15523
    Matched MeSH terms: Mutation, Missense
  12. Mat Ripen A, Ghani H, Chear CT, Chiow MY, Syed Yahya SNH, Kassim A, et al.
    SAGE Open Med, 2020;8:2050312120922652.
    PMID: 32547748 DOI: 10.1177/2050312120922652
    Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients.

    Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed.

    Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing.

    Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

    Matched MeSH terms: Mutation, Missense
  13. Lim KS, Tan AH, Lim CS, Chua KH, Lee PC, Ramli N, et al.
    PLoS One, 2015;10(8):e0135470.
    PMID: 26270344 DOI: 10.1371/journal.pone.0135470
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
    Matched MeSH terms: Mutation, Missense*
  14. Low VL, Vinnie-Siow WY, Lim Y AL, Tan TK, Leong CS, Chen CD, et al.
    Trop Biomed, 2015 Sep;32(3):554-6.
    PMID: 26695218 MyJurnal
    Given the lack of molecular evidence in altered target-site insecticide resistance mechanism in Aedes albopictus (Skuse) worldwide, the present study aims to detect the presence of A302S mutation in the gene encoding the gamma aminobutyric acid receptor resistant to dieldrin (Rdl) in Ae. albopictus for the first time from its native range of South East Asia, namely Malaysia. World Health Organization (WHO) adult susceptibility bioassay indicated a relatively low level of dieldrin resistance (two-fold) in Ae. albopictus from Petaling Jaya, Selangor. However, PCR-RFLP and direct sequencing methods revealed the presence of the A302S mutation with the predomination of heterozygous genotype (40 out of 82 individuals), followed by the resistant genotype with 11 individuals. This study represents the first field evolved instance of A302S mutation in Malaysian insect species.
    Matched MeSH terms: Mutation, Missense*
  15. Narayanan V, Veeramuthu V, Ahmad-Annuar A, Ramli N, Waran V, Chinna K, et al.
    PLoS One, 2016;11(7):e0158838.
    PMID: 27438599 DOI: 10.1371/journal.pone.0158838
    The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
    Matched MeSH terms: Mutation, Missense/genetics*
  16. Fu JYL, Chua CL, Vythilingam I, Sulaiman WYW, Wong HV, Chan YF, et al.
    J Gen Virol, 2019 11;100(11):1541-1553.
    PMID: 31613205 DOI: 10.1099/jgv.0.001338
    Chikungunya virus (CHIKV) has caused large-scale epidemics of fever, rash and arthritis since 2004. This unprecedented re-emergence has been associated with mutations in genes encoding structural envelope proteins, providing increased fitness in the secondary vector Aedes albopictus. In the 2008-2013 CHIKV outbreaks across Southeast Asia, an R82S mutation in non-structural protein 4 (nsP4) emerged early in Malaysia or Singapore and quickly became predominant. To determine whether this nsP4-R82S mutation provides a selective advantage in host cells, which may have contributed to the epidemic, the fitness of infectious clone-derived CHIKV with wild-type nsP4-82R and mutant nsP4-82S were compared in Ae. albopictus and human cell lines. Viral infectivity, dissemination and transmission in Ae. albopictus were not affected by the mutation when the two variants were tested separately. In competition, the nsP4-82R variant showed an advantage over nsP4-82S in dissemination to the salivary glands, but only in late infection (10 days). In human rhabdomyosarcoma (RD) and embryonic kidney (HEK-293T) cell lines coinfected at a 1 : 1 ratio, wild-type nsP4-82R virus was rapidly outcompeted by nsP4-82S virus as early as one passage (3 days). In conclusion, the nsP4-R82S mutation provides a greater selective advantage in human cells than in Ae. albopictus, which may explain its apparent natural selection during CHIKV spread in Southeast Asia. This is an unusual example of a naturally occurring mutation in a non-structural protein, which may have facilitated epidemic transmission of CHIKV.
    Matched MeSH terms: Mutation, Missense*
  17. Karunakaran R, Srikumar PS
    Mol Cell Biochem, 2018 Dec;449(1-2):55-62.
    PMID: 29532225 DOI: 10.1007/s11010-018-3342-8
    The crystallins are a family of monomeric proteins present in the mammalian lens and mutations in these proteins cause various forms of cataracts. The aim of our current study is to emphasize the structural characterization of aggregation propensity of mutation R58H on γD crystallin using molecular dynamics (MD) approach. MD result revealed that difference in the sequence level display a wide variation in the backbone atomic position, and thus exhibits rigid conformational dynamics. Changes in the flexibility of residues favoured to increase the number of intra-molecular hydrogen bonds in mutant R58H. Moreover, notable changes in the hydrogen bonding interaction resulted to cause the misfolding of mutant R58H by introducing α-helix. Principal component analysis (PCA) result suggested that mutant R58H showed unusual conformational dynamics along the two principal components when compared to the wild-type (WT)-γD crystallin. In a nutshell, the increased surface hydrophobicity could be the cause of self-aggregation of mutant R58H leading to aculeiform cataract.
    Matched MeSH terms: Mutation, Missense*
  18. Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, et al.
    Hum Mutat, 2019 09;40(9):1557-1578.
    PMID: 31131967 DOI: 10.1002/humu.23818
    The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
    Matched MeSH terms: Mutation, Missense*
  19. Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, et al.
    N Engl J Med, 2021 02 04;384(5):428-439.
    PMID: 33471991 DOI: 10.1056/NEJMoa1913948
    BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

    METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

    RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

    CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

    Matched MeSH terms: Mutation, Missense*
  20. Hung KL, Wang JS, Keng WT, Chen HJ, Liang JS, Ngu LH, et al.
    Pediatr Neurol, 2013 Sep;49(3):185-90.
    PMID: 23835273 DOI: 10.1016/j.pediatrneurol.2013.04.021
    X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids.
    Matched MeSH terms: Mutation, Missense/genetics*
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