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Fulltext Congenital insensitivity to pain with anhydrosis in a Malaysian family: a genetic analysis

Shalimar A, Sharaf I, Farah Wahida I, Ruszymah BH

J Orthop Surg (Hong Kong), 2007 Dec;15(3):357-60.
PMID: 18162686 DOI: 10.1177/230949900701500323

A Malaysian family with congenital insensitivity to pain with anhydrosis was diagnosed based on clinical symptoms of chronic ulcers, joint deformities, malunited fractures, anhydrosis, and learning disabilities. We detected a compound heterozygous mutation in exon 16: V709L from the mother and G718S from the father. Two novel mutations were identified: at amino acid 709, a change of G to C at nucleotide 2209 (approximately 2209G to C) causing a valine to leucine substitution (V709L), and at amino acid 718, a change of G to A at nucleotide 2236 (approximately 2236G to A) causing a glycine to serine substitution (G718S). Polymorphisms identified were at nucleotides approximately 2113G to C and approximately 2176T to C.

Matched MeSH terms: Pedigree
Fulltext Molecular characterization of two Malaysian patients with Wiskott-Aldrich syndrome

Baharin MF, Kader Ibrahim SB, Yap SH, Abdul Manaf AM, Mat Ripen A, Dhaliwal JS

Malays J Pathol, 2015 Aug;37(2):153-8.
PMID: 26277674 MyJurnal

The Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency condition characterized by microthrombocytopenia, eczema and recurrent infections. It is caused by mutations in the Wiskott-Aldrich Syndrome protein (WASP) gene. We investigated two Malay boys who presented with congenital thrombocytopenia, eczema and recurrent infections. Here we report two cases of WASP mutation in Malaysia from two unrelated families. One had a novel missense mutation in exon 1 while the other had a nonsense mutation in exon 2. Both patients succumbed to diseaserelated complications. A differential diagnosis of WAS should be considered in any male child who present with early onset thrombocytopenia, especially when this is associated with eczema and recurrent infections.

Matched MeSH terms: Pedigree
Fulltext X-linked hypophosphatemic rickets--a report of 2 cases and review of literature

Yong SM, Aik S

Med J Malaysia, 2000 Sep;55 Suppl C:101-4.
PMID: 11200035

We report two cases of x-linked dominant hypophosphatemic rickets involving a man and his daughter. The family tree consists of 44 members with 13 of them having short stature and bowing of the lower limbs. The study of this family tree strongly suggests an x-linked dominant inheritance.

Matched MeSH terms: Pedigree
A nonsense mutation in exon 8 of the APC gene (Arg283Ter) causes clinically variable FAP in a Malaysian Chinese family

Mohamed Z, Ahmad R, Yoke NS, Zakaria Z, Ahmad H, Yew TH

Cancer Sci, 2003 Aug;94(8):725-8.
PMID: 12901799 DOI: 10.1111/j.1349-7006.2003.tb01509.x

The present study was carried out to characterize the causative genetic mutation in a medium-sized Malaysian Chinese pedigree of three generations affected with familial adenomatous polyposis (FAP). Clinical data and genetic studies revealed considerable phenotypic variability in affected individuals in this family. Blood was obtained from members of the FAP-01 family and genomic DNA was extracted. Mutation screening of the adenomatous polyposis coli (APC) gene was carried out using the single strand conformation polymorphism (SSCP) technique. The possibility of exon skipping was predicted by splicing motif recognition software (ESEfinder release2.0). SSCP results showed mobility shifts in exon 8 of the APC gene which segregated with affected members of the family. Sequence analysis revealed that the affected individuals are heterozygous for a C847T transition, whilst all the unaffected family members and control individuals are homozygous C at the same position. This nucleotide substitution generates a stop codon at amino acid position 283, in place of the usual arginine (Arg283Ter). We conclude that an Arg283Ter mutation in the APC gene is causative of the FAP phenotype in this family, although there is considerable variation in the presentation of this disease among affected individuals. Computational analysis predicts that this mutation occurs within sequences that may function as splicing signals, so that the sequence change may affect normal splicing.

Matched MeSH terms: Pedigree
Fulltext Huntington disease: report of first case documented in Malaysia

Lee MK, Ng WK, Jeyakumar D

Med J Malaysia, 1994 Sep;49(3):297-300.
PMID: 7845285

Huntington disease has not previously been recorded in Malaysia. We report the first case in a local patient with a positive family history. The implications of diagnosing this disease will be discussed.

Matched MeSH terms: Pedigree
Fulltext Auricular sinus

Esa R, Solahuddin M

Med J Malaysia, 1993 Sep;48(3):286-92.
PMID: 8183140

A total of 56 subjects with auricular sinuses were investigated at the ENT clinic of University Kebangsaan Malaysia (UKM) from April 1986 to April 1987. Infection was the main complaint, accounting for 60% of the cases. Chinese formed the majority of the patients (51%) and the commonest age group was between 1 to 10 years. Multiple anomalies were seen more amongst the Indians and none were noted among the Chinese subjects. Hearing loss was noted in 6% of the cases. Only infected cases were operated and none showed recurrence.
Study site: ENT clinic, Pusat Perubatan University Kebangsaan Malaysia (PPUKM), Kualal Lumpur, Malaysia

Matched MeSH terms: Pedigree
Molecular characterization and nonradioactive detection of beta-thalassemia in Malaysia

Fucharoen S, Fucharoen G, Ata K, Aziz S, Hashim S, Hassan K, et al.

Acta Haematol., 1990;84(2):82-8.
PMID: 2120891 DOI: 10.1159/000205034

The spectrum of beta-thalassemia mutations in Malaysia has been determined in 45 beta-thalassemia chromosomes using dot blot hybridization of the polymerase chain reaction amplified DNA and direct DNA sequencing. Eleven different molecular defects, including those previously detected in Chinese, Asian Indians, and American blacks, and a novel frameshift mutation causing beta zero-thalassemia were detected. Since this novel mutation, a T deletion in codon 15 creates a new restriction site for EcoRII enzyme; the mutation could be detected by EcoRII digestion of the appropriate amplified fragment. The results of the present study provide additional information on the molecular heterogeneity of beta-thalassemia in this population. We also demonstrated the nonradioactive detection method of the beta-thalassemia mutation based upon the digoxigenin-labeled oligonucleotide probes.

Matched MeSH terms: Pedigree
Fulltext Cerebrotendinous xanthomatosis with cholestanolaemia--involvement of five individuals in a Malay family

Othman NH, Rahman SA

Med J Malaysia, 1990 Dec;45(4):275-80.
PMID: 2152046

Cerebrotendinous xanthomatosis (CTX), a rare inherited lipid storage disease is due to a defect in bile acid metabolism. Involvement of five members of a family is presented. The clinical features, laboratory and pathologic findings are discussed. Tendinous and tuberous xanthomatosis, bilateral cataracts, cerebral impairment and raised serum cholestanol are the salient features. We believe this is the first report of CTX in Malaysia.

Matched MeSH terms: Pedigree
Fulltext Homozygous haemoglobin E in association with hereditary ovalocytosis

George E, Kudva MV

Med J Malaysia, 1989 Sep;44(3):255-8.
PMID: 2626141

Hereditary stomatocytic ovalocytosis and haemoglobin E are two genes present in 3-5% of Malays. This is a report of a 22 year old Malay college student with homozygous haemoglobin E and hereditary stomatocytic ovalocytosis where the clinical effects seen were the result of the summation of these genes: he was asymptomatic, presenting with moderate jaundice, moderate hepatosplenomegaly, and a mild haemolytic anaemia.

Matched MeSH terms: Pedigree
Erythrocyte and leukocyte phosphoglucomutase in Chinese

Lie-Injo Luan Eng, Lopez CG, Poey-Oey Hoey Giok

Am J Hum Genet, 1968 Mar;20(2):101-6.
PMID: 5643177
Matched MeSH terms: Pedigree
DEPDC5 mutations in familial and sporadic focal epilepsy

Tsai MH, Chan CK, Chang YC, Yu YT, Chuang ST, Fan WL, et al.

Clin Genet, 2017 Oct;92(4):397-404.
PMID: 28170089 DOI: 10.1111/cge.12992

BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.
DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

Matched MeSH terms: Pedigree
Genetic Structure and Diversity Among Historic and Modern Populations of the Sumatran Rhinoceros (Dicerorhinus sumatrensis)

Brandt JR, van Coeverden de Groot PJ, Witt KE, Engelbrektsson PK, Helgen KM, Malhi RS, et al.

J Hered, 2018 06 27;109(5):553-565.
PMID: 29684146 DOI: 10.1093/jhered/esy019

The Sumatran rhinoceros (Dicerorhinus sumatrensis), once widespread across Southeast Asia, now consists of as few as 30 individuals within Sumatra and Borneo. To aid in conservation planning, we sequenced 218 bp of control region mitochondrial (mt) DNA, identifying 17 distinct mitochondrial haplotypes across modern (N = 13) and museum (N = 26) samples. Museum specimens from Laos and Myanmar had divergent mtDNA, consistent with the placement of western mainland rhinos into the distinct subspecies D. s. lasiotis (presumed extinct). Haplotypes from Bornean rhinos were highly diverse, but dissimilar from those of other regions, supporting the distinctiveness of the subspecies D. s. harrissoni. Rhinos from Sumatra and Peninsular Malaysia shared mtDNA haplotypes, consistent with their traditional placement into a single subspecies D. s sumatrensis. Modern samples of D. s. sumatrensis were genotyped at 18 microsatellite loci. Rhinos within Sumatra formed 2 sub-populations, likely separated by the Barisan Mountains, though with only modest genetic differentiation between them. There are so few remaining Sumatran rhinoceros that separate management strategies for subspecies or subpopulations may not be viable, while each surviving rhino pedigree is likely to retain alleles found in no other individuals. Given the low population size and low reproductive potential of Sumatran rhinos, rapid genetic erosion is inevitable, though an under-appreciated concern is the potential for fixation of harmful genetic variants. Both concerns underscore 2 overriding priorities for the species: 1) translocation of wild rhinos to ex situ facilities, and 2) collection and storage of gametes and cell lines from every surviving captive and wild individual.

Matched MeSH terms: Pedigree
Emergence of Getah Virus Infection in Horse With Fever in China, 2018

Lu G, Ou J, Ji J, Ren Z, Hu X, Wang C, et al.

Front Microbiol, 2019;10:1416.
PMID: 31281304 DOI: 10.3389/fmicb.2019.01416

Getah virus (GETV) is a mosquito-borne virus that was first determined in Malaysia in 1955, and can infect humans and multiple other mammals. GETV infection in horses has been reported in Japan and India, and causes great economic losses. In China, GETV has been identified in mosquitoes, pigs, foxes, and cattle with a wide geographical distribution, but has not been detected in horses. In August 2018, a sudden onset of fever was observed in racehorse in an equestrian training center in Guangdong Province in southern China. Blood samples were collected from the sick horse, and PCR/RT-PCR analysis was performed to screen for equine viral pathogens associated with fever. The results indicated that the samples were GETV RNA positive. After RT-PCR, sequencing, and assembly, the genome of the first Chinese horse-derived GETV strain, GZ201808, was obtained. Compared with the genome sequences of other GETV strains, twelve unique nucleotide substitutions were observed in GZ201808. The genome of GZ201808 had the highest genetic identity (99.6%) with AH9192, which was detected in pigs in China in 2017. Phylogenetic analysis indicated that GZ201808 clustered in Group III, and was located in an independent branch distant from other horse-derived GETV strains, indicating a unique evolutionary pattern of GZ201808. This study first determined and described the disease course of horse infected with GETV in China, sequenced and characterized the genome of the field horse-derived GETV strain, and therefore presented an unequivocal report of GETV infection in horses in China.

Matched MeSH terms: Pedigree
Fulltext Triallelic and epigenetic-like inheritance in human disorders of telomerase

Collopy LC, Walne AJ, Cardoso S, de la Fuente J, Mohamed M, Toriello H, et al.

Blood, 2015 Jul 09;126(2):176-84.
PMID: 26024875 DOI: 10.1182/blood-2015-03-633388

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.

Matched MeSH terms: Pedigree
Recessive distal renal tubular acidosis in Sarawak caused by AE1 mutations

Choo KE, Nicoli TK, Bruce LJ, Tanner MJ, Ruiz-Linares A, Wrong OM

Pediatr Nephrol, 2006 Feb;21(2):212-7.
PMID: 16252102

Mutations of the AE1 (SLC4A1, Anion-Exchanger 1) gene that codes for band 3, the renal and red cell anion exchanger, are responsible for many cases of familial distal renal tubular acidosis (dRTA). In Southeast Asia this disease is usually recessive, caused either by homozygosity of a single AE1 mutation or by compound heterozygosity of two different AE1 mutations. We describe two unrelated boys in Sarawak with dRTA associated with compound heterozygosity of AE1 mutations. Both had Southeast Asian ovalocytosis (SAO), a morphological abnormality of red cells caused by a deletion of band 3 residues 400-408. In addition, one boy had a DNA sequence abnormality of band 3 residue (G701D), which has been reported from elsewhere in Southeast Asia. The other boy had the novel sequence abnormality of band 3 (Q759H) and profound hemolytic anemia.

Matched MeSH terms: Pedigree
Hidrotic ectodermal dysplasia: study of a large Chinese pedigree

Rajagopalan K, Tay CH

Arch Dermatol, 1977 Apr;113(4):481-5.
PMID: 139851

Hidrotic ectodermaldysplasia was found, to our knowledge, for the first time in a Chinese family in Malaysia, and it affected 15 members in five generations. The disease, which is transmitted as a non-sex-linked autosomal dominant trait, presumably originated from southern China. All 15 members had the typical nail, hair, and skin lesions, and we observed three different types of nail defects. Scalp alopeica was more extensive in the female members while keratoderma of the palms and soles was more notable in the male members. The nail and skin lesions also became severer with age. Except for the infectious eczematoid dermatitis present in the propositus, none had other skin or systemic disorders. All were relatively healthy and had normal life expectancies;

Matched MeSH terms: Pedigree
Whole exome sequencing identifies a novel SCN1A mutation in genetic (idiopathic) generalized epilepsy and juvenile myoclonic epilepsy subtypes

Chan CK, Low JS, Lim KS, Low SK, Tan CT, Ng CC

Neurol Sci, 2020 Mar;41(3):591-598.
PMID: 31720899 DOI: 10.1007/s10072-019-04122-9

INTRODUCTION: Genetic (idiopathic) generalized epilepsy (GGE) is a common form of epilepsy characterized by unknown aetiology and a presence of genetic component in its predisposition.
METHODS: To understand the genetic factor in a family with GGE, we performed whole exome sequencing (WES) on a trio of a juvenile myoclonic epilepsy/febrile seizure (JME/FS) proband with JME/FS mother and healthy father. Sanger sequencing was carried out for validation of WES results and variant detection in other family members.
RESULTS: Predictably damaging variant found in affected proband and mother but absent in healthy father in SCN1A gene was found to be associated with generalized epilepsy and febrile seizure. The novel non-synonymous substitution (c.5753C>T, p.S1918F) in SCN1A was found in all family members with GGE, of which 4/8 were JME subtypes, and/or febrile seizure, while 3 healthy family member controls did not have the mutation. This mutation was also absent in 41 GGE patients and 414 healthy Malaysian Chinese controls.
CONCLUSION: The mutation is likely to affect interaction between the sodium channel and calmodulin and subsequently interrupt calmodulin-dependent modulation of the channel.

Matched MeSH terms: Pedigree
A case of beta-thalassemia with a C----T substitution at position 654 of the second intervening sequence of the beta-globin gene

Jo T, Momita S, Sadamori N, Tomonaga M, Fucharoem S, Fukumaki Y, et al.

Intern. Med., 1992 Feb;31(2):269-72.
PMID: 1600278

A 26-year-old Chinese-Malaysian female patient with beta-thalassemia is presented. The main hematological values found in this patient were as follows: 1) normocytic hypochromic anemia (RBC 444 x 10(4)/microliters, Hb 11.8 g/dl) with marked anisopoikilocytosis, 2) erythroid hyperplasia, and 3) increased HbF (HbA 41.4%, HbA2 2.9%, HbF 48.9%). DNA obtained from peripheral leukocytes was analyzed using dot blot hybridization of the polymerase chain reaction (PCR)-amplified DNA with allele-specific oligonucleotide probes. A C----T substitution at position 654 of the second intervening sequence (IVS-2) was detected in her beta-globin clone.

Matched MeSH terms: Pedigree
Functional characterization of two variants in the 3'-untranslated region (UTR) of transcription factor 4 gene and their association with schizophrenia in sib-pairs from multiplex families

Mohamed ZI, Tee SF, Chow TJ, Loh SY, Yong HS, Bakar AKA, et al.

Asian J Psychiatr, 2019 Feb;40:76-81.
PMID: 30771755 DOI: 10.1016/j.ajp.2019.02.001

Transcription factor 4 (TCF4) gene plays an important role in nervous system development and it always associated with the risk of schizophrenia. Since miRNAs regulate targetgenes by binding to 3'UTRs of target mRNAs, the functional variants located in 3'UTR of TCF4 are highly suggested to affect the gene expressions in schizophrenia. To test the hypothesis regarding the effects of the variants located in 3'UTR of TCF4, we conducted an in silico analysis to identify the functional variants and their predicted functions. In this study, we sequenced the 3'UTR of TCF4 in 13 multiplex schizophrenia families and 14 control families. We found two functional variants carried by three unrelated patients. We determined that the C allele of rs1272363 and the TC insert of rs373174214 might suppress post- transcriptional expression. Secondly, we cloned the region that flanked these two variants into a dual luciferase reporter system and compared the luciferase activities between the pmirGLO-TCF4 (control), pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263. Both pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263 caused lower reporter gene activities, as compared to the control. However, only the C allele of rs1272363 reduced the luciferase activity significantly (p = 0.0231). Our results suggested that rs1273263 is a potential regulator of TCF4 expression, and might be associated with schizophrenia.

Matched MeSH terms: Pedigree
3-Methylglutaconic aciduria, a frequent but underrecognized finding in carbamoyl phosphate synthetase I deficiency

Rokicki D, Pajdowska M, Trubicka J, Thong MK, Ciara E, Piekutowska-Abramczuk D, et al.

Clin Chim Acta, 2017 Aug;471:95-100.
PMID: 28526534 DOI: 10.1016/j.cca.2017.05.023

The urea cycle disorder carbamoyl phosphate synthetase I deficiency is an important differential diagnosis in the encephalopathic neonate. This intoxication type inborn error of metabolism often leads to neonatal death or severe and irreversible damage of the central nervous system, even despite appropriate treatment. Timely diagnosis is crucial, but can be difficult on routine metabolite level. Here, we report ten neonates from eight families (finally) diagnosed with CPS1 deficiency at three tertiary metabolic centres. In seven of them the laboratory findings were dominated by significantly elevated urinary 3-methylglutaconic acid levels which complicated the diagnostic process. Our findings are both important for the differential diagnosis of patients with urea cycle disorders and also broaden the differential diagnosis of hyperammonemia associated with 3-methylglutaconic aciduria, which was earlier only reported in TMEM70 and SERAC1 defect.

Matched MeSH terms: Pedigree

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