The term "campomelic" comes from the Greek words for "bent limb." Affected individuals are typically born with bowing of the long bones in the legs, and occasionally, bowing in the arms. Bowing can cause characteristic skin dimples to form over the curved bone, especially on the lower legs. People with campomelic dysplasia usually have short legs, dislocated hips, underdeveloped shoulder blades, 11 pairs of ribs instead of 12, bone abnormalities in the neck, and inwardand upward-turning feet (clubfeet). These skeletal abnormalities begin developing before birth and can often be seen on ultrasound. When affected individuals have features of this disorder but do not have bowed limbs, they are said to have acampomelic campomelic dysplasia.
Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) interactions with lipids, proteins and other mechanisms of human body. Production of RMs mainly superoxide (O2−) has been found in a variety of predominating cellular enzyme systems including NAD(P)H oxidase, xanthine oxidase (XO), cyclooxygenase (COX), uncoupled endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO). The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), nitric oxide synthase (NOS) are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in pathogenesis of T2DM individuals. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiate stress related pathways thereby leading to insulin resistance and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM.
BACKGROUND:Down syndrome (DS) is the most common cause of mental retardation of genetic etiology with the prevalence rate of 1/700 to 1/1000 live births worldwide. Several polymorphisms in folate/homocysteine metabolism pathways genes have been reported as a risk factor in women for bearing DS child, but very few studies investigated these polymorphisms in DS cases whether there are a risk factor for being DS or not.OBJECTIVE:We have investigated the association of methylenetetrahydrofolate reductase (MTHFR) with the occurrence of DS in Indian population. MTHFR is one of the key regulatory enzymes involved in the metabolic pathway of homocysteine responsible for the reduction of methyltetrahydrofolate. A total of 32 DS cases and 64 age, sex matched controls were genotyped for MTHFR C677T polymorphism by polymerase chain reaction-restriction fragment length polymorphism.RESULTS:The observed genotype frequencies were CC = 0.81; CT = 0.17 and TT = 0.02 in controls and CC = 0.81 and CT = 0.19 in DS cases. Frequency of T allele in DS and controls were 0.09 and 0.1, respectively. Significant difference in the distribution of mutant 677T allele was not observed between DS cases and controls (odds ratio = 0.915; 95% confidence intervals: 0.331-2.53; P = 0.864).CONCLUSION:Results of this study indicate that MTHFR C677T polymorphism is not risk factor for DS.
Cooks syndrome is characterized by familial congenital anonychia or onychodystrophy, hypoplasia or absence of distal phalanges of the hands and feet with brachydactyly of the fifth finger and digitalization of the thumb (triphalangism). It is listed as a "rare disease" by the Office of Rare Diseases of the National Institutes of Health. Here, we report a case of congenital anonychia and brachydactyly of the left foot, which possibly is a variant of Cooks syndrome with a positive family history of similar deformity.
209 Sir, This is in reference to our article published in Indian Journal of Human Genetics titled “Evaluation of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and its association with levels of serum homocysteine, folate, and Vitamin B12 as maternal risk factors for Down syndrome (DS)”.[1] We found a genuine relationship between maternal folate and MTHFR gene polymorphism in <3 months infants, which was not analyzed in the original article. In DS mothers with baby <3 months, red blood cell (RBC) folate were significantly lower than controls, but not in case of serum folate. Though association with polymorphism was not statistically significant, but gave us a trend [Table 1]. Lower RBC folate in mothers with baby <3 months possibly denotes status at conception.[2] RBC folate is a preferred marker to assess long-term folate status. Data’s from the selected randomized controlled trials showed that folic acids with dietary folate supply exerted a significant effect on all the markers of folate status, especially for RBC folate.[3] Similarly, a meta-analysis by Mohamed[4] showed that routine folate supplementation in pregnancy resulted in a substantial reduction in the incidence of low serum and Letter to the Editor
1 Familial Mediterranean fever (FMF) is an unusual and rare disease. In this disease paroxysms of fever lasting for few days coupled with inflammation of serous membranes such as peritoneal, pericard pleural, synovial and meningeal coverings are inflamed. Some of patients develop inflammation related amyloidosis (AA amyloidosis) with all its attendant consequences.[1] Although the disease is now known for almost more than a century in the limited geographical areas of middle eastern countries, Turkey and Egypt. Sporadically this disease has been described from many parts of the world.[2] The biology of the disease is only being understood for last two decades[3] and the mutations of the disease causing gene are being increasingly identified and reported regularly in an international database.[4]
MATERIALS AND METHODS:The genetic diversity and forensic parameters based on 15 autosomal short tandem repeats (STR) loci; D8S1179,D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317,D16S539, D2S1338, D19S433, vWA, TPOX, D18S51,D5S818, and FGA in AmpFLSTR® Identifiler™ kit from Applied Biosystems, Foster City, CA, USA were evaluated in saliva samples of 297 unrelated individuals from the Bhil Tribe population of Gujarat state, India to study genetic diversities and relatedness of this population with other national and international populations.RESULTS:Statistical analysis of the data revealed all loci were within Hardy-Weinberg Equilibrium expectations with the exception of the locus vWA (0.019) and locus D18S51 (0.016). The neighbour joining phylogeny tree and Principal Co-ordinate Analysis plot constructed based on Fst distances from autosomal STRs allele frequencies of the present study and other national as well as international populations show clustering of all the South Asian populations in one branch of the tree, while Middle Eastern and African populations cluster in a separate branch.CONCLUSION:Our findings reveal strong genetic affinities seen between the Indo-European (IE) speaking Bhil Tribe of Gujarat and Dravidian groups of South India.
Chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence. Chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1, 9, 16 and Y and the short arms of all acrocentric chromosomes. Here, we report a girl with Down-syndrome such as facies and tremendously enlarged short arm of a chromosome 22. Fluorescence in situ hybridization (FISH) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm. Parental studies identified a maternal origin of this heteromorphism. Cryptic trisomy 21 of the Down-syndrome critical region was excluded by a corresponding FISH-probe. Here, we report, to the best of our knowledge, largest ever seen chromosome 22 short arm, being ~×1.5 larger than the normal long arm.
BACKGROUND:Down's syndrome is an important congenital chromosomal disorder that can be seen around the world. The antenatal screening for this disorder is an important processing in present obstetrics.OBJECTIVE:Due to the concept of first do no harm, the use of noninvasive test is recommended. The triple marker screening test has been introduced for a few years and acceptable for its efficacy.RESULT:However, an important concern is on its cost-effectiveness. Here, the author analyze and present the cost-effectiveness of the triple markers serum screening for Down's syndrome in Thai setting.CONCLUSION:According to this work, the cost per effectiveness of triple markers serum screening is slightly lower than standard amniocentesis test.
So far, more than 1800 mutations identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In this case report, we presented first report of c. 1499G>C mutation in a 6-month-old girl with cystic fibrosis (CF) diagnosis. A 6-month-old girl with weakness and meconium Ileus referred to the pediatric clinic in Ilam, in the west of Iran. Patient's skin was dark and suffered from bronchiectasis. The sweat test was performed, and the concentration of chloride and sodium in patient's sweat was 130-135 mmol/L and 125-128 mmol/L, respectively. The exon 10 mutation analysis of a CF patient was performed. CFTR mutation analysis revealed the identification of 2 mutations in patient, the mutations were p.F508del (ΔF508) and c. 1499G>C (cd500), respectively. The mutation c. 1499G>C (cd500) were found for the first time in the world. Assessing this mutation in future study and genetic investigation is recommended.
Patients with 13q deletion syndrome are characterized with different phenotypical features depending on the size and location of the deleted region on chromosome 13. These patients fall into three groups: In Group 1, deleted region is in the proximal and does not extend into q32; in Group 2, deleted region involves proximal to the q32 and in Group 3 q33-q34 is deleted. We present two cases with 13q syndrome with two different deleted region and different severity on clinical features: One case with interstitial deletion belongs to the Group 1 with mild mental retardation and minor malformations and the other case with terminal deletion belongs to Group 3 with moderate to severe mental retardation and major malformations.
Background: Acute promyelocytic leukemia (APL) with t (15;17) is a distinct category of acute myeloid leukemia (AML) and is reported to show better response to anthracyclin based chemotherapy. A favorable overall prognosis over other subtypes of AML has been reported for APL patients but still about 15% patients relapse. Methods: This study evaluated the presence of Famus like tyrosine kinase-3 (FLT3) and nucleophosmin-1 (NPM1) gene mutations in a cohort of 40 APL patients. Bone marrow/peripheral blood samples from patients at the time of diagnosis and follow-up were processed for immunophenotyping, cytogenetic markers and isolation of DNA and RNA. Samples were screened for the presence of mutations in FLT3 and NPM1 genes using polymerase chain reaction followed by sequencing. Results: Frequency of FLT3/internal tandem duplication and FLT3/tyrosine kinase domain was found to be 25% and 7% respectively. We observed a high frequency of NPM1 mutation (45%) in the present population of APL patients.
BACKGROUND:BCR-ABL fusion oncogene is a hallmark of Chronic Myeloid Leukemia (CML). It results due to translocation between chromosome 22 and chromosome 9 [t (9; 22)(q34; q11)]. It gives rise to translation of a 210 KDa chimeric protein (p210), leading to enhanced tyrosine kinase activity and activation of leukemogenic pathways, ultimately causing onset of CML. In case of CML, the classic fusions are b2a2 or b3a2, fusing exon 13 (b2) or exon 14 (b3) of BCR, respectively, to exon 2 (a2) of ABL. The type of BCR-ABL transcripts are thought to be have different prognosis and hence useful in clinical decision-making. The frequencies of different fusion oncogenes associated with leukemia can vary in different ethnic groups and geographical regions due to interplay of genetic variation in different ethnic populations, diverse environmental factors and living style. Moreover, earlier relevant studies from our region were carried out in small subset of patients. Therefore, objective of this study was to find out frequencies of different BCR-ABL splice variants in larger subset of CML patients.METHODS:A nested reverse transcriptase polymerase chain reaction (RT-PCR) was established to detect BCR-ABL splice variants in 130 CML patients. Sensitivity of RT-PCR and ability to detect BCR-ABL fusion gene in least possible time was studied.RESULTS:BCR-ABL detection using our optimized RT-PCR protocol could be completed in 8 hours, starting from RNA extraction to Gel electrophoresis. Sensitivity of RT-PCR assay was of the order of 10(-6). Out of 130 Pakistani patients, 83 (63.84%) expressed b3a2 while 47 (36.15%) expressed b2a2 transcript.CONCLUSION:Our RT-PCR was proved to be very quick to detect BCR-ABL fusion oncogene in CML patients within one working day. Because of its sensitivity, it can be used to monitor complete molecular response in CML. BCR-ABL RT-PCR and BCR-ABL splice variants frequency in our study differs from other ethnic groups. It shows that ethnic and geographical differences exist in BCR-ABL splice variant frequency, which may have a profound effect on disease biology as well as implications in prognosis and clinical management of BCR-ABL positive leukemias.
The β-thalassemias and sickle cell disorders are a major health burden in India. Diagnosis and management of these disorders both in adults and in newborns using appropriate approaches and uniform technology are important in different regions of a vast and diverse country as India. In view of a National Thalassemia Control Program to be launched soon, a need was felt for guidelines on whom to screen, cost-effective technologies that are to be used as well as for establishing prenatal diagnosis programs in regional centers. Newborn screening for sickle cell disorders is in its infancy in India and uniform approaches need to be followed. Also, included are guidelines for monitoring and managing patients who are now growing older and need comprehensive care as well as management of complications of the disease.
BACKGROUND AND AIM:This study reports the prevalence of five clinically significant variants associated with increased risk of cardiovascular disorders, and variable responses of individuals to commonly prescribed cardiovascular drugs in a South Indian population from the state of Kerala.MATERIALS AND METHODS:Genomic DNA isolated from 100 out-patient samples from Kerala were sequenced to examine the frequency of clinically relevant polymorphisms in the genes MYBPC3 (cardiomyopathy), SLCO1B1 (statin-induced myopathy), CYP2C9, VKORC1 (response to warfarin) and CYP2C19 (response to clopidogrel).RESULTS:Our analyses revealed the frequency of a 25 bp deletion variant of MYBPC3 associated with risk of cardiomyopathy was 7%, and the SLCO1B1 "C" allele associated with risk for statin-induced myopathy was 15% in this sample group. Among the other variants associated with dose-induced toxicity of warfarin, VKORC1 (c.1639G>A), was detected at 22%, while CYP2C9*3 and CYP2C9*2 alleles were present at a frequency of 15% and 3% respectively. Significantly, the tested sample population showed high prevalence (66%) of CYP2C19*2 variant, which determines response to clopidogrel therapy.CONCLUSIONS:We have identified that certain variants associated with cardiovascular disease and related drug response in the five genes, especially those in VKORC1, CYP2C19 and MYBPC3, are highly prevalent in the Kerala population, with almost 2 times higher prevalence of CYP2C19*2 variant compared with other regions in the country. Since the variants chosen in this study have relevance in disease phenotype and/or drug response, and are detected at a higher frequency, this study is likely to encourage clinicians to perform genetic testing before prescribing therapy.
We report a case of Wildervanck syndrome exhibiting Klippel-Feil anomaly, Duane's retraction syndrome and congenital deafness. Since the first case was reported in 1952, there have been more reports describing this triad either complete or incomplete. Our case has a complete triad of the syndrome along with frontal sinus hypoplasia. Our case is unique as the triad was associated with frontal sinus hypoplasia, which is very rare association.
The evolutionary conserved, less-polymorphic, nonclassical major histocompatibility complex (MHC) class I molecules: Qa-1 and its human homologue human leukocyte antigen-E (HLA-E) along with HLA-F, G and H cross-talk with the T-cell receptors and also interact with natural killer T-cells and other lymphocytes. Moreover, these nonclassical MHC molecules are known to interact with CD94/NKG2 heterodimeric receptors to induce immune responses and immune regulations. This dual role of Qa-1/HLA-E in terms of innate and adaptive immunity makes them more interesting. This review highlights the new updates of the mammalian nonclassical MHC-I molecules in terms of their gene organization, evolutionary perspective and their role in immunity.
Folate is an essential B vitamin that provides one-carbon molecules for DNA synthesis, protein synthesis, and methylation of DNA and proteins. The folate pathway plays a critical role in cellular function and human development, as evidenced by the association between maternal folic acid intake and the risk of neural tube defects, cardiovascular disease, and cancer.[1] Both nutrient status and genetic background are independent but interacting risk factors for these disorders. However, the biochemical and developmental mechanisms that lead to pathology or the mechanisms whereby folate prevents the occurrence and recurrence of these disorders are unknown. The methylenetetrahydrofolatereductase (MTHFR) gene (677C → T) is a common polymorphism which results in reduced MTHFR enzyme activity that leads to reduced capacity to remethylate homocysteine and generate S-adenosyl methionine and hypomethylated lymphocytic DNA. Two studies in this issue found no association of MTHFR C677T polymorphism with the disease condition. Pandey et al.[2] studied MTHFR 677CT polymorphism in craniosynostosis and found no association with the disease. The other study in this issue found no association of MTHFR 677CT polymorphism in Down syndrome (DS) children, however, it was linked to clinical severity such as low IQ.[3] In general, maternal folate metabolism associated with fetal disease condition. Several studies were carried out on maternal MTHFR 677CT polymorphism and nondisjunction of trisomy 21. James et al.[4] were the first to suggest a role of the folate pathway in chromosome 21 nondisjunction as the major cause of DS. They showed that the C677T polymorphism associated biochemical changes in folate pathway metabolites in mothers, were associated with a 2.6-fold increased chance of having a child with trisomy 21. Some subsequent studies examining the relationship between maternal folate metabolism and delivering a child with DS found no link with genetic variants in single folate pathway genes, whereas others pointed to an additive effect with variants in multiple genes.[5] Since maternal folic acid supplementation can modify the effect of genetic variants in the folate pathway, a lack of maternal folic acid supplementation is a potential risk factor for chromosome 21 nondisjunction. The studies on intake of folic acid and risk of DS are contradictory. The research groups observed a significantly reduced association between trisomy 21 and maternal folic acid supplement intake three or more times a week at least 1 week before conception. It was hypothesized that the environmental factors, like maternal exposure to folic acid, may influence chromosome segregation at different times during oocyte development. In females, the formation of oocytes is initiated during fetal life and is not completed until decades later. Meiosis I (MI) begins at around 12 weeks of gestation in the mother’s fetal life, at which time chromosomes replicate, and homologs pair and undergo recombination. At approximately 20 weeks in maternal fetal life, MI arrests in prophase, and this arrest is not released until ovulation, Access this article online Quick Response Code: Website: www.ijhg.com
Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis-1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.
BACKGROUND: Many studies have been conducted to identify either insertions-deletions (inDels) or copy number variations (CNVs) in humans, but few studies have been conducted to identify both of these forms coexisting in the same region. AIMS AND OBJECTIVES: To map the functionally significant sites within human genes that are likely to influence human traits and diseases. MATERIALS AND METHODS: In this report, we describe an inDel map in the 1051 Tibetan CNV regions obtained through CNV genotyping using Affymetrix Genome-wide single nucleotide polymorphism 6.0 chip. InDel polymorphisms in these copy number polymorphism regions were identified with a computational approach using the 2500 deoxyribonucleic acid sequences obtained from the 1000 Genome Project. RESULTS: The study identified a total of 95935 inDels that range from 1 bp to several bps in length which were found scattered across regulatory regions, exons and in introns of genes underlying the CNVs. A study on the distribution of inDels revealed that the majority of inDels were found in coding regions of the genome than the noncoding, while within the genes, inDels in intron regions were more followed by exonic regions and finally the regulatory regions. CONCLUSION: Study of inDels in CNV regions contribute to the enhanced understanding of the role played by the two variations and their collective influence on the genome. Further, a collection of these inDel genetic markers will aid in genetic mapping, further understanding of the phenotypic variability, identification of disease genes and in detecting novel CNVs.
