Publications by authors named "Keng Wee Teik"

18 Publications

  • Page 1 of 1

Oncologist-led counselling improves access to cancer genetic testing in middle-income Asian country, with no significant impact on psychosocial outcomes.

J Med Genet 2021 Feb 1. Epub 2021 Feb 1.

Gynaeoncology, Hospital Wanita Dan Kanak-Kanak Sabah, Kota Kinabalu, Malaysia.

Background: Identifying patients with mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming.

Methods: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.

Results: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in or and there was no difference between psychosocial measures for carriers in both arms.

Conclusion: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.
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http://dx.doi.org/10.1136/jmedgenet-2020-107416DOI Listing
February 2021

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study.

Orphanet J Rare Dis 2019 06 14;14(1):143. Epub 2019 Jun 14.

Genetics Department, Hospital Kuala Lumpur, Ministry of Health Malaysia, Jalan Pahang, 50586, Kuala Lumpur, Malaysia.

Background: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce.

Methods: This is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients.

Results: The patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia - 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified.

Conclusions: All the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.
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http://dx.doi.org/10.1186/s13023-019-1105-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570902PMC
June 2019

Intron retention is among six unreported AGL mutations identified in Malaysian GSD III patients.

Genes Genomics 2019 08 26;41(8):885-893. Epub 2019 Apr 26.

Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia.

Background: Glycogen storage disease type III is an autosomal recessive disorder that is caused by deficiencies of the glycogen debranching enzyme. Mutations within the AGL gene have been found to be heterogeneous, with some common mutations being reported in certain populations. The mutation spectrum of AGL gene in the multi-ethnic Malaysian population is still unknown.

Objective: The present study seeks to determine the mutation spectrum of the AGL gene in Malaysian population.

Methods: A total of eleven patients (eight Malay, two Chinese and one Bajau) were investigated. Genomic DNA was extracted and subsequently the AGL gene was amplified using specific primers and sequenced. Mutations found were screened in 150 healthy control samples either by restriction enzyme digestion assay or TaqMan SNP Genotyping assay.

Results: We identified six unreported mutations (c.1423+1G>T, c.2914_2915delAA, c.3814_3815delAG, c.4333T>G, c.4490G>A, c.4531_4534delTGTC) along with three previously reported mutations (c.99C>T, c.1783C>T, c.2681+1G>A). One of the six unreported mutation causes abnormal splicing and results in retention of intron 12 of the mature transcript, while another is a termination read-through. One of the reported mutation c.2681+1G>A was recurrently found in the Malay patients (n = 7 alleles; 31.8%).

Conclusion: The mutation spectrum of the AGL gene in Malaysian patients has shown considerable heterogeneity, and all unreported mutations were absent in all 150 healthy control samples tested.
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http://dx.doi.org/10.1007/s13258-019-00815-9DOI Listing
August 2019

Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: Clinical and molecular findings in Malaysian patients.

Pediatr Neonatol 2018 08 13;59(4):397-403. Epub 2017 Nov 13.

Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia. Electronic address:

Background: Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive inborn error of gluconeogenesis. We reported the clinical findings and molecular genetic data in seven Malaysian patients with FBPase deficiency.

Methods: All patients diagnosed with FBPase deficiency from 2010 to 2015 were included in this study. Their clinical and laboratory data were collected retrospectively.

Results: All the patients presented with recurrent episodes of hypoglycemia, metabolic acidosis, hyperlactacidemia and hepatomegaly. All of them had the first metabolic decompensation prior to 2 years old. The common triggering factors were vomiting and infection. Biallelic mutations in FBP1 gene (MIM*611570) were identified in all seven patients confirming the diagnosis of FBPase deficiency. In four patients, genetic study was prompted by detection of glycerol or glycerol-3-phosphate in urine organic acids analysis. One patient also had pseudo-hypertriglyceridemia. Seven different mutations were identified in FBP1, among them four mutations were new: three point deletions (c.392delT, c.603delG and c.704delC) and one splice site mutation (c.568-2A > C). All four new mutations were predicted to be damaging by in silico analysis. One patient presented in the neonatal period and succumbed due to sepsis and multi-organ failure. Among six survivors (current age ranged from 4 to 27 years), four have normal growth and cognitive development. One patient had short stature and another had neurological deficit following status epilepticus due to profound hypoglycemia.

Conclusion: FBPase deficiency needs to be considered in any children with recurrent hypoglycemia and metabolic acidosis. Our study expands the spectrum of FBP1 gene mutations.
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http://dx.doi.org/10.1016/j.pedneo.2017.11.006DOI Listing
August 2018

Combination of Multiple Ligation-Dependent Probe Amplification and Illumina MiSeq Amplicon Sequencing for TSC1/TSC2 Gene Analyses in Patients with Tuberous Sclerosis Complex.

J Mol Diagn 2017 03 11;19(2):265-276. Epub 2017 Jan 11.

Center for Neuroscience Services and Research, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia; Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate. Thirty-four Malaysian patients diagnosed with TSC were referred to Human Genome Center, Universiti Sains Malaysia. We used a combination of MLPA to detect large copy number changes and AS to detect smaller mutations. TSC1 pathogenic or likely pathogenic mutations were found in 6 patients (18%) and TSC2 in 21 patients (62%), whereas 6 patients (18%) show no mutations and 1 patient (2%) showed only TSC2 missense variant with uncertain significance. Six of the mutations are novel. Our detection strategy costs 81% less and require 1 working week less than the conventional strategy. Confirmatory sequencing using Sanger method on a few representative mutations showed agreement with results of the AS. Combination of MLPA and Illumina MiSeq AS provides a simplified strategy and reasonably high detection rate for TSC1/TSC2 mutation, which suggested application of the strategies into clinical molecular diagnostics.
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http://dx.doi.org/10.1016/j.jmoldx.2016.10.009DOI Listing
March 2017

Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges.

J Pediatr Endocrinol Metab 2016 Sep;29(9):1031-9

Background: The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia.

Methods: During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing.

Results: Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively.

Conclusions: IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.
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http://dx.doi.org/10.1515/jpem-2016-0028DOI Listing
September 2016

FAT1 mutations cause a glomerulotubular nephropathy.

Nat Commun 2016 Feb 24;7:10822. Epub 2016 Feb 24.

Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada M5G 1X8.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.
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http://dx.doi.org/10.1038/ncomms10822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770090PMC
February 2016

Spectrum of germ-line RB1 gene mutations in Malaysian patients with retinoblastoma.

Mol Vis 2015 14;21:1185-90. Epub 2015 Oct 14.

Department of Ophthalmology, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur, Malaysia.

Purpose: The availability of molecular genetic testing for retinoblastoma (RB) in Malaysia has enabled patients with a heritable predisposition to the disease to be identified, which thus improves the clinical management of these patients and their families. In this paper, we presented our strategy for performing molecular genetic testing of the RB1 gene and the findings from our first 2 years of starting this service.

Methods: The peripheral blood of 19 RB probands, including seven bilateral and 12 unilateral cases, was obtained, and genomic DNA was extracted. Analysis of the RB1 exons and the promoter region was conducted first using PCR and direct sequencing. Next, multiplex ligation-dependent probe amplification (MLPA) analysis was performed for patients whom the first results were negative. For patients whom either the first or second method results were positive, parental samples were analyzed to determine the origin of the mutation.

Results: Ten RB1 mutations were identified in ten (52.6%) of the 19 probands (seven bilateral and three unilateral cases), of which 30.0% (3/10) was identified with MLPA. The detection rates in the bilateral and unilateral cases were 100.0% (7/7) and 25.0% (3/12), respectively. Three new RB1 mutations were discovered, two in patients with bilateral RB and one in patient with unilateral RB. Interestingly, all mutations detected with the PCR-sequencing method were predicted to create a premature stop codon. Eight mutations were proven to be de novo while one mutation was inherited from the mother in a family with a positive history of RB.

Conclusions: Our results confirmed the heterogeneous nature of RB1 mutations and the predominantly de novo origin. The high prevalence of pathogenic truncating mutations was evident among local patients with RB. The combination of PCR sequencing and MLPA is recommended for sensitive identification of heritable RB cases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605750PMC
June 2016

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care.

Genet Med 2016 05 23;18(5):483-93. Epub 2015 Jul 23.

Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK.

Purpose: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established.

Methods: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians.

Results And Conclusion: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.
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http://dx.doi.org/10.1038/gim.2015.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857186PMC
May 2016

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Am J Med Genet A 2015 Feb 16;167A(2):296-312. Epub 2015 Jan 16.

INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes - Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
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http://dx.doi.org/10.1002/ajmg.a.36887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382202PMC
February 2015

Two novel gross deletions of TSC2 in Malaysian patients with tuberous sclerosis complex and TSC2/PKD1 contiguous deletion syndrome.

Jpn J Clin Oncol 2014 May 30;44(5):506-11. Epub 2014 Mar 30.

*Center for Neuroscience Services and Research, and Human Genome Center, School of Medical Sciences, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder affecting multiple organs. Tuberous sclerosis complex is caused by mutation in either one of the two disease-causing genes, TSC1 or TSC2, encoding for hamartin and tuberin, respectively. TSC2/PKD1 contiguous gene deletion syndrome is a very rare condition due to deletion involving both TSC2 and PKD1 genes. Tuberous sclerosis complex cannot be easily diagnosed since there is no pathognomonic feature, although there are consensus diagnostic criteria for that. Mutation analysis is useful and plays important roles. We report here two novel gross deletions of TSC2 gene in Malay patients with tuberous sclerosis complex and TSC2/PKD1 contiguous gene deletion syndrome, respectively.
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http://dx.doi.org/10.1093/jjco/hyu024DOI Listing
May 2014

Mutational analyses on X-linked adrenoleukodystrophy reveal a novel cryptic splicing and three missense mutations in the ABCD1 gene.

Pediatr Neurol 2013 Sep 5;49(3):185-90. Epub 2013 Jul 5.

School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan ROC.

Background: 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.

Methods: Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families.

Results: A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121 bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands.

Conclusions: This is the first report to unveil unequivocally that cryptic splicing-induced aberrant messenger-RNA carrying an internal frameshift deletion results from an intronic mutation in the ABCD1 gene. Furthermore, a polymorphism in intron 9 (c.1992-32c/t; refSNP: rs4898368) of the ABCD1 gene was commonly observed in both Taiwanese and Malaysian populations.
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http://dx.doi.org/10.1016/j.pediatrneurol.2013.04.021DOI Listing
September 2013

Clinical features and respiratory complications in Myhre syndrome.

Eur J Med Genet 2011 Nov-Dec;54(6):e553-9. Epub 2011 Jul 21.

Ferguson-Smith Dept. of Clinical Genetics, Yorkhill Hospital, Glasgow, UK.

We describe the clinical characteristics of 4 singleton cases, 3 males and 1 female, with Myhre Syndrome (OMIM 139210), who were born to non-consanguineous parents. Three cases had no family history of similarly affected individuals but 1 male's mother had short stature, some facial features suggestive of Myhre syndrome and evidence of skewed X-chromosome inactivation in her blood DNA. Short stature, deafness, learning difficulties, skeletal anomalies and facial dysmorphisms were evident in all cases. Arthralgia and stiff joints with limited movement were also present. The facial appearance, thickened skin, a 'muscular' habitus are memorable features. The female patient was least affected: this patient and one affected male displayed streaky skin with areas of patchy thickening, suggestive of genetic mosaicism. One patient developed sleep apnoea, a restrictive ventilatory defect and died following a choking episode. Another affected male developed recurrent, progressive, proximal, tracheal stenosis requiring partial tracheal resection, laser treatment and eventually tracheotomy. Review of Myhre syndrome patients in the literature and syndromes in the differential diagnosis, suggests heterogeneity in Myhre syndrome and clinical overlap with Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2011.07.001DOI Listing
January 2012

Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): a case series of 11 Malaysian patients.

J Inherit Metab Dis 2010 Dec 16;33 Suppl 3:S489-95. Epub 2010 Dec 16.

Genetic and Metabolic Unit, Department of Paediatrics, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia.

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.
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http://dx.doi.org/10.1007/s10545-010-9248-6DOI Listing
December 2010

Novel heterozygous mutations in TALDO1 gene causing transaldolase deficiency and early infantile liver failure.

J Pediatr Gastroenterol Nutr 2011 Jan;52(1):113-6

Department of Genetics, Pediatric Institute, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia.

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http://dx.doi.org/10.1097/MPG.0b013e3181f50388DOI Listing
January 2011

Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype.

Hum Mutat 2010 Sep;31(9):1059-68

Institute of Human Genetics, Charitè Universitätsmedizin, Berlin, Germany.

We have previously shown that mutations in the genes encoding DNA Ligase IV (LIGIV) and RAD50, involved in DNA repair by nonhomologous-end joining (NHEJ) and homologous recombination, respectively, lead to clinical and cellular features similar to those of Nijmegen Breakage Syndrome (NBS). Very recently, a new member of the NHEJ repair pathway, NHEJ1, was discovered, and mutations in patients with features resembling NBS were described. Here we report on five patients from four families of different ethnic origin with the NBS-like phenotype. Sequence analysis of the NHEJ1 gene in a patient of Spanish and in a patient of Turkish origin identified homozygous, previously reported mutations, c.168C>G (p.Arg57Gly) and c.532C>T (p.Arg178Ter), respectively. Two novel, paternally inherited truncating mutations, c.495dupA (p.Asp166ArgfsTer20) and c.526C>T (p.Arg176Ter) and two novel, maternal genomic deletions of 1.9 and 6.9 kb of the NHEJ1 gene, were found in a compound heterozygous state in two siblings of German origin and in one Malaysian patient, respectively. Our findings confirm that patients with NBS-like phenotypes may have mutations in the NHEJ1 gene including multiexon deletions, and show that considerable clinical variability could be observed even within the same family.
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http://dx.doi.org/10.1002/humu.21315DOI Listing
September 2010

Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.

Hum Mol Genet 2006 May 16;15(9):1413-22. Epub 2006 Mar 16.

Medical Genetics Section, MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.

We report heterozygous, loss-of-function SOX2 mutations in three unrelated individuals with Anophthalmia-Esophageal-Genital (AEG) syndrome. One previously reported case [Rogers, R.C. (1988) Unknown cases. Proceedings of the Greenwood Genetic Center. 7, 57.] has a 2.7 Mb deletion encompassing SOX2 and associated with a cryptic translocation t(3;7)(q28;p21.3). The deletion and translocation breakpoints on chromosome 3q are >8.6 Mb apart and both chromosome rearrangements have occurred de novo. Another published case [Petrackova et al. (2004) Association of oesophageal atresia, anophthalmia and renal duplex. Eur. J. Pediatr., 163, 333-334.] has a de novo nonsense mutation, Q55X. A previously unreported case with severe bilateral microphthalmia and oesophageal atresia has a de novo missense mutation, R74P, that alters a highly evolutionarily conserved residue within the high mobility group domain, which is critical for DNA-binding of SOX2. In a yeast one-hybrid assay, this mutation abolishes Sox2-induced activation of the chick delta-crystallin DC5 enhancer. Four other reported AEG syndrome cases were extensively screened and do not have detectable SOX2 mutations. Two of these cases have unilateral eye malformations. SOX2 mutations are known to cause severe bilateral eye malformations but this is the first report implicating loss of function mutations in this transcription factor in oesophageal malformations. SOX2 is expressed in the developing foregut in mouse and zebrafish embryos and an apparently normal pattern of expression is maintained in Shh-/- mouse embryos, suggesting either that Sox2 acts upstream of Shh or functions in a different pathway. Three-dimensional reconstructions of the major morphological events in the developing foregut and eye from Carnegie Stages 12 and 13 human embryos are presented and compared with the data from model organisms. SOX2, with NMYC and CHD7, is now the third transcriptional regulator known to be critical for normal oesophageal development in humans.
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http://dx.doi.org/10.1093/hmg/ddl064DOI Listing
May 2006