Displaying publications 1 - 20 of 124 in total

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  1. Fulltext Germline TET2 loss of function causes childhood immunodeficiency and lymphoma
    Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al.
    Blood, 2020 Aug 27;136(9):1055-1066.
    PMID: 32518946 DOI: 10.1182/blood.2020005844
    Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
    Matched MeSH terms: Pedigree
  2. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation
    Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, et al.
    Eur J Prev Cardiol, 2015 Jul;22(7):849-54.
    PMID: 24776375 DOI: 10.1177/2047487314533218
    Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.
    Matched MeSH terms: Pedigree
  3. Analysis of Hereditary Nonpolyposis Colorectal Cancer in Malay Cohorts using Immunohistochemical Screening
    Wan Juhari WK, Wan Abdul Rahman WF, Mohd Sidek AS, Abu Hassan MR, Ahmad Amin Noordin KB, Zakaria AD, et al.
    Asian Pac J Cancer Prev, 2015;16(9):3767-71.
    PMID: 25987035
    BACKGROUND: Lynch syndrome (LS) is an inherited predisposition to colorectal, endometrial (uterine) and other cancers. Although most cancers are not inherited, about 5 percent (%) of people who have colorectal or endometrial cancer have the Lynch syndrome. It involves the alteration of mismatch repair (MMR) genes; MLH1, MSH2, MSH6 or PMS2. In this study, we analyzed the expression of MMR proteins in colorectal cancer in a Malay cohort by immunohistochemistry.

    MATERIALS AND METHODS: A total of 17 patients were selected fulfilling one of the Bethesda criteria: colorectal cancer diagnosed in a patient aged less than 50 years old, having synchronous and metachronous colorectal cancer or with a strong family history. Immunohistochemical staining was performed on paraffin embedded tumour tissue samples using four antibodies: MLH1, MSH2, MSH6 and PMS2.

    RESULTS: Twelve out of 17 patients (70.6%) were noted to have a family history. A total of 41% (n=7) of the patients had abnormal immunohistochemical staining with one or more of the four antibodies. Loss of expression were noted in 13 tumour tissues with a negative staining score <4. Of 13 tumour tissues, four showed loss expression of MLH1. For PMS2, loss of expression were noted in five cases. Both MSH2 and MSH6 showed loss of expression in two tumour tissues respectively.

    CONCLUSIONS: Revised Bethesda criteria and immunohistochemical analysis constituted a convenient approach and is recommended to be a first-line screening for Lynch syndrome in Malay cohorts.

    Matched MeSH terms: Pedigree
  4. Fulltext Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D
    Shmukler BE, Kedar PS, Warang P, Desai M, Madkaikar M, Ghosh K, et al.
    Am J Hematol, 2010 Oct;85(10):824-8.
    PMID: 20799361 DOI: 10.1002/ajh.21836
    Familial distal renal tubular acidosis (dRTA) can be caused by mutations in the Cl2/HCO32 exchanger of the renal Type A intercalated cell, kidney AE1/SLC4A1. dRTA-associated AE1 mutations have been reported in families from North America, Europe, Thailand, Malaysia, Papua-New Guinea, Taiwan, and the Philippines, but not India. The dRTA mutation AE1 A858D has been detected only in the context of compound heterozygosity. We report here two unrelated Indian patients with combined hemolytic anemia and dRTA who share homozygous A858D mutations of the AE1/SLC4A1 gene. The mutation creates a novel restriction site that is validated for diagnostic screening.
    Matched MeSH terms: Pedigree
  5. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease
    Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, et al.
    Nat Genet, 2019 08;51(8):1222-1232.
    PMID: 31332380 DOI: 10.1038/s41588-019-0458-z
    Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
    Matched MeSH terms: Pedigree
  6. Cardiovascular risk factors in pre-pubertal Malays: effects of diabetic parentage
    Choo KE, Lau KB, Davis WA, Chew PH, Jenkins AJ, Davis TM
    Diabetes Res Clin Pract, 2007 Apr;76(1):119-25.
    PMID: 16979774 DOI: 10.1016/j.diabres.2006.08.006
    Diabetes prevalence is increasing rapidly in Asian populations but the influence of a family history of diabetes on cardiovascular risk is unknown. To assess this relationship, 120 urban-dwelling Malays were recruited to a cross-sectional case-control study. Sixty were pre-pubertal children, 30 of diabetic parentage (Group 1) and 30 with no diabetes family history (Group 2). Group 1 and 2 subjects were the offspring of adults with (Group 3) or without (Group 4) type 2 diabetes. Subjects were assessed for clinical and biochemical variables defining cardiovascular risk. Principal component analysis assessed clustering of variables in the children. Group 1 subjects had a higher mean waist:hip ratio, diastolic blood pressure and HbA(1c) than those in Group 2, and a lower HDL:total cholesterol ratio (P<0.03). Although there were no correlations between Group 1 and 3 subjects for cardiovascular risk variables, significant associations were found in Groups 2 and 4, especially HbA(1c) and insulin sensitivity (P< or =0.004). Of five separate clusters of variables (factors) identified amongst the children, the strongest comprised diabetic parentage, HbA(1c), insulin sensitivity and blood pressure. Features of the metabolic syndrome are becoming evident in the young non-obese children of diabetic Malays, suggesting that lifestyle factors merit particular attention in this group.
    Matched MeSH terms: Pedigree
  7. A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction
    Sakamoto M, Kouhei D, Haniffa M, Silva S, Troncoso M, Santander P, et al.
    J Hum Genet, 2020 Sep;65(9):751-757.
    PMID: 32405030 DOI: 10.1038/s10038-020-0765-3
    Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.
    Matched MeSH terms: Pedigree
  8. Fulltext Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy
    Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al.
    Am J Hum Genet, 2016 Oct 06;99(4):950-961.
    PMID: 27666374 DOI: 10.1016/j.ajhg.2016.08.005
    We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.
    Matched MeSH terms: Pedigree
  9. Clinical significance of SLC2A9/GLUT9 rs11722228 polymorphisms in gout
    Das Gupta E, Sakthiswary R, Lee SL, Wong SF, Hussein H, Gun SC
    Int J Rheum Dis, 2018 Mar;21(3):705-709.
    PMID: 27456670 DOI: 10.1111/1756-185X.12918
    AIM: The main objective of this study is to elucidate the clinical significance of the SLC2A9/GLUT9 rs11722228 polymorphism among male gout patients.
    METHOD: We consecutively recruited all newly diagnosed male gout patients who were treatment-naive from the rheumatology outpatient clinics of two Malaysian hospitals. Age-matched healthy male adults were employed as controls. All subjects were tested for the SLC2A9/GLUT9 rs11722228 genotypes, serum uric acid (SUA), urine uric acid and creatinine levels. All gout subjects were examined for the presence of tophi and sonographically screened for renal calculi.
    RESULTS: A total of 73 male gout patients and 73 age-matched healthy male adults were recruited in this study. The genotypic frequencies of SLC2A9/GLUT9 rs1172228 did not differ significantly between the gout cases and the healthy controls. The gout subjects with the CC genotype had significantly higher SUA levels (P = 0.002), family history of gout (P < 0.050) and the occurrence of renal calculi (P = 0.026). The SUA-adjusted odds ratios (OR) of the occurrence of renal calculi in the CC genotype (OR = 1 [reference]) was significantly higher than the CT genotype (OR = 0.338, 95%CI: 0.141-0.813) and the TT genotype (OR = 0.271, 95%CI: 0.086-0.854).
    CONCLUSIONS: The genotypic distribution of SLC2A9/GLUT9 rs1172228 in male gout patients did not differ significantly from that of healthy male controls. However, the CC genotype in gout had significant associations with higher levels of SUA, renal calculi and a positive family history of gout.
    Study site: Rheumatology clinic, Tuanku Jaafar Hospital, Malaysia and Putrajaya Hospital, Malaysia
    Matched MeSH terms: Pedigree
  10. Fulltext Discovery of candidate genes for nonsyndromic cleft lip palate through genome-wide linkage analysis of large extended families in the Malay population
    Mohamad Shah NS, Salahshourifar I, Sulong S, Wan Sulaiman WA, Halim AS
    BMC Genet, 2016 Feb 11;17:39.
    PMID: 26868259 DOI: 10.1186/s12863-016-0345-x
    BACKGROUND: Nonsyndromic orofacial clefts are one of the most common birth defects worldwide. It occurs as a result of genetic or environmental factors. This study investigates the genetic contribution to nonsyndromic cleft lip and/or palate through the analysis of family pedigrees. Candidate genes associated with the condition were identified from large extended families from the Malay population.

    RESULTS: A significant nonparametric linkage (NPL) score was detected in family 100. Other suggestive NPL and logarithm of the odds (LOD) scores were attained from families 50, 58, 99 and 100 under autosomal recessive mode. Heterogeneity LOD (HLOD) score ≥ 1 was determined for all families, confirming genetic heterogeneity of the population and indicating that a proportion of families might be linked to each other. Several candidate genes in linkage intervals were determined; LPHN2 at 1p31, SATB2 at 2q33.1-q35, PVRL3 at 3q13.3, COL21A1 at 6p12.1, FOXP2 at 7q22.3-q33, FOXG1 and HECTD1 at 14q12 and TOX3 at 16q12.1.

    CONCLUSIONS: We have identified several novel and known candidate genes for nonsyndromic cleft lip and/or palate through genome-wide linkage analysis. Further analysis of the involvement of these genes in the condition will shed light on the disease mechanism. Comprehensive genetic testing of the candidate genes is warranted.

    Matched MeSH terms: Pedigree
  11. Fulltext Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome
    Ariffin H, Hainaut P, Puzio-Kuter A, Choong SS, Chan AS, Tolkunov D, et al.
    Proc Natl Acad Sci U S A, 2014 Oct 28;111(43):15497-501.
    PMID: 25313051 DOI: 10.1073/pnas.1417322111
    The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.
    Matched MeSH terms: Pedigree
  12. Fulltext Investigation of a PAX6 gene mutation in a Malaysian family with congenital aniridia
    Lee PC, Lam HH, Ghani SA, Subrayan V, Chua KH
    Genet. Mol. Res., 2014;13(2):3553-9.
    PMID: 24737507 DOI: 10.4238/2014.March.24.15
    Mutations in the PAX6 gene that cause aniridia have been identified in various ethnicities but not in the Malaysian population. Therefore, the objective of this study was to investigate the PAX6 mutation in a Malaysian family with congenital aniridia. In this study, a complete ophthalmic examination was performed on a Dusun ethnic family with aniridia. Genomic DNA was extracted from the peripheral blood of the subjects and screened for the PAX6 gene mutation using polymerase chain reaction amplification high-resolution melting curve analysis (PCR-HRM) followed by confirmation via direct DNA sequencing. A heterozygous G deletion (c.857delG) in exon 7 causing a frame shift in PAX6 was identified in all affected family members. Genotype-phenotype correlation analysis revealed congenital cataract and all affected family members showed a similar spectrum of aniridia with no phenotypic variability but with differences in severity that were age-dependent. In summary, by using a PCR-HRM approach, this study is the first to report a PAX6 mutation in a Malaysian family. This mutation is the cause of the aniridia spectra observed in this family and of congenital cataract.
    Matched MeSH terms: Pedigree
  13. Fulltext Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients
    Khositseth S, Bruce LJ, Walsh SB, Bawazir WM, Ogle GD, Unwin RJ, et al.
    QJM, 2012 Sep;105(9):861-77.
    PMID: 22919024 DOI: 10.1093/qjmed/hcs139
    Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations.
    Matched MeSH terms: Pedigree
  14. Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): a case series of 11 Malaysian patients
    Chew HB, Ngu LH, Zabedah MY, Keng WT, Balasubramaniam S, Hanifah MJ, et al.
    J Inherit Metab Dis, 2010 Dec;33 Suppl 3:S489-95.
    PMID: 21161389 DOI: 10.1007/s10545-010-9248-6
    Citrin deficiency, aetiologically linked to mutations of SLC25A13 gene, has two clinical phenotypes, namely adult-onset type II citrullinaemia (CTLN2) and neonatal/infantile intrahepatic cholestasis, caused by citrin deficiency (NICCD). Malaysian patients with NICCD, especially of Malay and East Malaysian indigenous descent, have never been reported in the literature. We present the clinical features, biochemical findings and results of molecular analysis in 11 Malaysian children with NICCD. In this case series, all patients manifested prolonged cholestatic jaundice and elevated citrulline levels. The other more variable features included failure to thrive, bleeding diathesis, hypoproteinaemia, abnormal liver enzymes, prolonged coagulation profile, hyperammonaemia, hypergalactosaemia, multiple aminoacidaemia, elevated α-feto protein and urinary orotic acid as well as liver biopsies showing hepatitis and steatosis. DNA analysis of SLC25A13 revealed combinations of 851del4(Ex9), IVS16ins3kb and 1638ins23. Most of our patients recovered completely by the age of 22 months. However, one patient had ongoing symptoms at the time of reporting and one had died of liver failure. Since a small percentage of children with NICCD will develop CTLN2 and the mechanisms leading to this is yet to be defined, ongoing health surveillance into adulthood is essential.
    Matched MeSH terms: Pedigree
  15. A negative waveform in the scotopic response in a patient with phosphoglycerate kinase deficiency: a visual electrophysiology report
    Mohd Khialdin S, Grigg J, Rowe N, Crofts S, Wilson M, Troedson C
    Documenta ophthalmologica. Advances in ophthalmology, 2015 Dec;131(3):215-20.
    PMID: 26396085 DOI: 10.1007/s10633-015-9511-0
    Phosphoglycerate kinase (PGK) deficiency is an X-linked neurometabolic genetic disorder with variable systemic manifestations. So far, only one patient with retinal anomalies has been reported, but no visual electrophysiology findings were described. We report the first description of visual electrophysiology in a child with PGK deficiency. This provides further information for the site of involvement in the eye.
    Matched MeSH terms: Pedigree
  16. Mild beta-thalassemia intermedia caused by compound heterozygosity for (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia and molecular characterization of the defect in four Chinese families
    Tan JAMA, Yap SF, Tan KL, Wong YC, Wee YC, Kok JL
    Acta Haematol., 2003;109(4):169-75.
    PMID: 12853688 DOI: 10.1159/000070965
    Molecular characterization of the compound heterozygous condition - (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia - in four families showing mild beta-thalassemia intermedia was carried out using DNA amplification techniques. Using the Amplification Refractory Mutation System (ARMS) to confirm the beta-mutations and DNA amplification to detect the 100-kb Chinese-specific (G)gamma((A)gammadeltabeta)(o)-deletion, ()two families were confirmed to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia with the IVSII No. 654 beta(+)-allele. In the third family, the (G)gamma((A)gammadeltabeta)(o)-deletion was confirmed in the father and the mother was a beta-thalassemia carrier with the cd 41-42 beta(o)-allele. Their affected child with (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia was found to be transfusion dependent. The same (G)gamma((A)gammadeltabeta)(o)-deletion and beta-thalassemia (cd 41-42) was also confirmed in a fourth family. In addition, the mother was also diagnosed with Hb H disease (genotype -alpha(3.7)/-(SEA)). Both the children were found to possess (G)gamma((A)gammadeltabeta)(o)/beta-thalassemia but they were not transfusion dependent and this could be due to co-inheritance of alpha-thalassemia-2 (genotype-alpha(3.7)/alphaalpha) in the children together with their compound heterozygous condition.
    Matched MeSH terms: Pedigree
  17. Fulltext Thyroid carcinoma in patients with familial adenomatous polyposis
    Rohaizak M, Jasmi AY, Ismail MA, Munchar MJ, Meah FA
    Asian J Surg, 2003 Jul;26(3):183-5.
    PMID: 12925296 DOI: 10.1016/S1015-9584(09)60381-X
    There has been a growing awareness of the association between papillary thyroid carcinoma and familial adenomatous polyposis (FAP). The cases of four young patients with papillary thyroid carcinoma occurring with FAP are presented. Three patients underwent surgery to provide specimens for detailed histological examination. The surgical specimens showed well-encapsulated multicentric tumours exhibiting a predominantly papillary architectural growth pattern. In some areas, follicular architecture and cribriform patterns were noted. Atypical areas of spindle cells in a trabecular or solid configuration, which are not normally seen in classical papillary thyroid carcinoma, were evident. Malignant cells exhibited a graduation of cuboidal to tall cells with abundant amphophilic cytoplasm. The nuclei did not exhibit the typical nuclear clearing as seen in papillary thyroid carcinoma, but nuclear grooving and inclusions were noted. Psammoma bodies were not seen in any of the specimens. In a limited review of these patients, features such as young age at presentation, multicentricity and unusual histology suggest that thyroid carcinoma associated with FAP may represent a distinct form of thyroid cancer.
    Matched MeSH terms: Pedigree
  18. Psychiatric morbidity in the first-degree relatives of schizophrenic patients
    Varma SL, Zain AM, Singh S
    Am. J. Med. Genet., 1997 Feb 21;74(1):7-11.
    PMID: 9033998
    There is increasing evidence that genetic factors play a role in the etiology of schizophrenic disorders. One thousand eighty-nine first-degree relatives of schizophrenics and 1,137 controls were studied to discover their psychiatric morbidity. Psychiatric morbidity was found in 16.34% of the first-degree relatives (FDR) of schizophrenics (parents, 5.69%; siblings, 7.71%; offspring, 2.94%) as compared to 6.9% in the controls (P < 0.001). Schizophrenia was found in 8.3% of the patient group, which was significantly higher (0.2%) as compared to the controls. Schizoid-schizotypal personality disorder was found in 3.03% of FDRs of the schizophrenic group. Depressive disorder was found in 4.4% and 2.1% in the control and patient group, respectively, which was statistically significant. Morbidity risk of schizophrenia was found in 16.97%, 6.22% and 5.79% of schizophrenia, schizoid-schizotypal personality disorder and depressive disorder, respectively, in the FDR of schizophrenic group.
    Matched MeSH terms: Pedigree
  19. Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families
    Kang P, Mariapun S, Phuah SY, Lim LS, Liu J, Yoon SY, et al.
    Breast Cancer Res Treat, 2010 Nov;124(2):579-84.
    PMID: 20617377 DOI: 10.1007/s10549-010-1018-5
    Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2.
    Matched MeSH terms: Pedigree
  20. Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing
    Ng PS, Wen WX, Fadlullah MZ, Yoon SY, Lee SY, Thong MK, et al.
    Clin Genet, 2016 10;90(4):315-23.
    PMID: 26757417 DOI: 10.1111/cge.12735
    Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations.
    Matched MeSH terms: Pedigree
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