Articles written in Journal of Genetics

    • Novel mutations in the transmembrane natriuretic peptide receptor NPR-B gene in four Indian families with acromesomelic dysplasia, type Maroteaux


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      Acromesomelic dysplasia, type Maroteaux is a disorder characterized by disproportionate short stature predominantly affecting the middle and distal segments of the upper and lower limbs. It is an autosomal recessive disorder due to mutation in NPR2 gene which impairs skeletal growth. To screen the mutations in the gene NPR2, all of its coding exons and splice junction sites were PCR amplified from genomic DNA of affected individuals of four families and sequenced. Four homozygous mutations in four different families were identified. These include three novel mutations including a deletion frameshift mutation (p.Cys586Ter), one nonsense mutation (p.Arg479Ter), one missense mutation (p.Val187Asp) and one reported missense mutation (p.Tyr338Cys). The study describes phenotypes of Indian patients and expands the mutation spectrum of the disorder.

    • Study of the association of forkhead box P3 (FOXP3) gene polymorphisms with unexplained recurrent spontaneous abortions in Indian population


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      Recurrent spontaneous abortions (RSA) is defined as three or more consecutive pregnancy losses before 20 weeks of gestation. Various causes of RSA have been identified, still 50% cases remain unexplained after evaluation. One of the causes of unexplained recurrent spontaneous abortions (URSA) is supposed to be the disruption of immunological tolerance at foetaen-dashmaternal interface. Regulatory T cells (Tregs) are responsible for the development of immune-tolerant environment at foetalen-dashmaternal interface and supports pregnancy. Forkhead/winged helix transcription factor (FOXP3) gene plays an important role in the development and function of Tregs. In URSA, Tregs (CD4+CD25+) are reduced in peripheral blood and decidua of pregnant women. This reduction of Tregs (CD4+CD25+) is associated with decreased expression of FOXP3 gene. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in FOXP3 gene and URSA in Indian population. In this study, 100 patients with a history of URSA and 100 healthy ethnically matched women with at least one normal pregnancy and no abortion were included as case and control groups, respectively. Four SNPs of FOXP3 gene, two in the promoter region: −924A/G and −3279C/A , and two intronic, −20G/A and +459T/C , were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). −924A/G and +459T/C polymorphisms were found to be associated with URSA. −3279C/A and −20G/A polymorphism were not found to be associated with URSA. The odds ratio (OR) of mutant allele G for −924A/G polymorphism was 2.5 (95% CI 1.7–3.8; P<0.001 ) and mutant allele C for +459T/C polymorphism was 1.7 (95% CI 1.1en-dash2.6; P=0.01 ). For −20G/A polymorphism, only GG genotype was found in both URSA and controls. These results suggest that −924A/G and +459T/C polymorphisms of the FOXP3 gene might be associated with URSA and −20G/A polymorphism is likely to be rare in Indian population and might not be associated with URSA.

    • Gene expression profiling of coronary artery disease and its relation with different severities


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      Global gene expression profiling is a powerful tool enabling the understanding of pathophysiology and subsequent management of diseases. This study aims to explore functionally annotated differentially expressed genes (DEGs); their biological processes for coronary artery disease (CAD) and its different severities of atherosclerotic lesions. This study also aims to identify thechange in expression patterns of DEGs in atherosclerotic lesions of single-vessel disease (SVD) and triple-vessel disease (TVD). The weight of different severities of lesion was estimated using a modified Gensini score. The gene expression profiling was performed using the Affymetrix microarray platform. The functional annotation for CAD was performed using DAVID v6.8. The biological network gene ontology tool (BiNGO) and ClueGO were used to explore the biological processes of functionally annotated genes of CAD. The changes in gene expression from SVD to TVD were determined by evaluating the fold change. Functionally annotated genes were found in an unique set and could be distinguishing two distinct severities of CAD. The biological processes such ascellular migration, locomotion, cell adhesion, cytokine production, positive regulation of cell death etc. enriched the functionally annotated genes in SVD, whereas, wound healing, negative regulation of cell death, blood coagulation, angiogenesis and fibrinolysis were enriched significantly in TVD patients. The genes THBS1 and CAPN10 were functionally annotated for CAD in both SVD and TVD. The 61 DEGs were identified, those have changes their expression with different severities of atherosclerotic lesions, in which 13 genes had more than two-fold change in expression between SVD and TVD. The consistent findings were obtained on validation of microarray gene expression of selected 10 genes in a separate cohort using real-time PCR. This study identified putative candidategenes and their biological processes predisposing toward and affecting the severity of CAD.

    • Cytogenetic microarray in structurally normal and abnormal foetuses: a five year experience elucidating in creasing acceptance and clinical utility


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      The aim of the present study was to evaluate the diagnostic yield of prenatal cytogeneticmicroarray (CMA) in structurally normal and abnormal foetuses and record the acceptance rate of CMA for prenatal diagnosis over a course of five year. In 128 structurally normal and abnormal foetuses, CMA was performed along with foetal karyotype, after exclusion of aneuploidy by quantitative fluorescence polymerase chain reaction. The microarray was able to detect the pathogenic variants in 5.5% cases; the diagnostic yield in structurally abnormal foetuses was 8.8% and 4.7% in foetuses with a high aneuploidy risk. Balanced and unbalanced translocations, and low level mosaicism were detected. Reanalysis of variants of uncertain significance identified pathogenic variant. The study shows higher diagnostic yield in structurally abnormal cases, the importance of foetal karyotype and reanalysis in microarray. The acceptance rate of prenatal CMA increased five-fold over a period of five year.

    • Hypotonic infant with Pallister–Killian syndrome diagnosed by cytogenetic microarray, without pigmentary skin changes and malformations


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      Pallister–Killian syndrome (PKS) is a rare genetic developmental disorder characterized, by intellectual disability, seizures,streaks of hypo- or hyperpigmentation and characteristic dysmorphic features. PKS is characterized by the presence of cytogenetic abnormality in form of a supernumerary isochromosome 12p, in a tissue limited mosaicism. The isochromosome 12p is usually not detected in karyotype done from peripheral blood. Presence of patchy pigmentary skin lesions suggest the possibility of mosaicism and karyotype from skin is done which clinches the diagnosis. We describe an infant with severe hypotonia in whom trisomy 12p was detected bychromosomal microarray performed on peripheral blood. The karyotype from blood was normal and combining this information with three copies of 12p in microarray suggests the possibility of tetrasomy12p in mosaic form. The infant did not have any skin patchy pigmentary changes and malformations and hence, the diagnosis of PKS was not clinically suspected. Cytogenetic microarray is the first test for evaluation of cases with developmental delay and intellectual disability, PKS diagnosis may come as a surprise in unsuspected caseswithout characteristic skin pigmentary abnormality and malformations.

    • Homozygosity stretches around homozygous mutations in autosomal recessive disorders: patients from nonconsanguineous Indian families


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      India has a large heterogeneous population with its unique social and genetic characteristics. Tradition of marriage betweenspecific caste groups have produced unique characteristics to the mutation spectrum of genetic disorders and may be a higher prevalence ofautosomal recessive (AR) disorders in some communities. We observed that in many nonconsanguineous families with rare autosomaldisorders, maternally and paternally inherited mutations are same, indicating common ancestor. In this era of genomic techniques, findinghomozygous regions have become easy. It was seen that the patients with AR disorders, who were homozygous for the disease causingpathogenic / likely pathogenic variations, have large stretches (0.6–188 Mb) of homozygosity around the causative sequence variations.SNP microarray data of patients from consanguineous and nonconsanguineous families also showed that even patients from nonconsanguineousfamilies had 3–49 Mb size regions of homozygosity. Long stretches of homozygosity around homozygous rare pathogenicvariants in nonconsanguineous families with rare AR disorders supports the notion that these couples may have a common ancestor formore than six generations and the system of marriages between same groups. Hence, using the strategy of homozygosity by descent even innonconsanguineous families can be fruitful in identifying the novel pathogenic variations and novel genes.

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