A Novel Familial Case Report of Genetic Syndrome Mimicking Congenital TORCH infections; Pseudo-TORCH Syndrome 2.

Background: Pseudo-TORCH syndrome (PTS) is a group of autosomal recessive disorders that clinically and radiologically mimic TORCH congenital infections. The prevalence of pseudo-TORCH syndrome 2 is 1 in 1,000,000 cases worldwide. This novel disorder is extremely rare, and is generally detected by prenatal diagnosis through next generation sequencing (NGS) during pregnancy. In this study, a familial case of pseudo-TORCH syndrome 2 with novel non-sense mutation in the ubiquitin-specific peptidase 18 (USP 18) gene in the parents was reported, who are heterozygous asymptomatic carriers; however, all children have inherited a homozygous pathogenic form of USP18, which is an important negative regulator of type I interferon (IFN) signal transduction. To the best of our knowledge, this is the first case of a novel mutation of USP18 seen in a family with pseudo-TORCH syndrome 2 (PTS 2) from India. Case Presentation: A 23-year-old pregnant woman with bad obstetric history, including intrauterine and neonatal mortality was referred to the Institute of Genetics in the year 2021 for clinical and genetic evaluation. Advanced clinical exome sequencing of the parents and the fetus revealed heterozygous carrier status in parents and homozygous mutation in USP 18 gene in the progeny leading to pseudo-TORCH-2 syndrome. Conclusion: The present case highlights the significance of carrier screening, prenatal diagnosis, and genetic counseling in couples with bad obstetric history for the detection of rare genetic disorders with poor prognosis.

BRIP1/FANCJ Mutation Analysis in a Family with History of Male and Female Breast Cancer in India.

Male breast cancer (MBC) is a rare and poorly studied disease that is a growing global health problem. Interestingly, both the molecular basis of MBC and its histological profile are often quite distinct from the far more prevalent female breast cancer, emphasizing the need for increased focus on MBC. Here, we present a case report of an MBC patient from India with a strong familial history of breast cancer. This patient was normal for BRCA1/2 and many other common breast cancer-associated genes. However, upon further analysis, the individual was found to possess two mutations in the DNA helicase and tumor suppressor gene BRIP1, including a silent mutation at residue 879 as well as a P919S variant. Other family members were also screened for these mutations. To the best of our knowledge, this is the first report of BRIP1 mutation in MBC in the Indian population.

Heat shock protein 70 gene polymorphisms' influence on the electrophysiology of long QT syndrome.

PURPOSE: Long QT syndrome (LQTS) is a rare cardiac disorder caused due to mutations in genes encoding ion channels responsible for generation of electrical impulses. The heat shock protein (HSP)-70 gene, expressed under conditions of stress, plays a cardioprotective role when overexpressed and helps in the proper folding of the nascent proteins synthesized by the cellular machinery. We aimed to identify the role played by HSP-70 gene polymorphisms in the pathogenesis of LQTS. METHODS: Study included 49 LQTS patients, 71 family members, and 219 healthy individuals recruited from an ethnically matched population. Genotyping of the single-nucleotide polymorphisms (SNPs) rs1043618 (HSP-70-1, +190G/C), rs1061581 (HSP-70-2, +1267A/G), and rs2227956 (HSP-70-hom, +2437T/C) was performed by PCR-RFLP analysis, and the results were analyzed statistically at 95 % confidence interval and p ≤ 0. 05. RESULTS: The "C" allele of HSP-70-1 (+190G/C) and "G" allele of HSP-70-2 (+1267A/G) showed strong association with LQTS phenotype. The haplotype group C-G-T consisting of two risk alleles was significantly associated with the disease condition. Multifactor dimensionality reduction analysis further substantiated that the three-allele model influences the outcome of the phenotype highlighting the effect of modifiers in the etiology of LQTS. CONCLUSIONS: As HSP-70 influences the channel assembly and maturation/trafficking of the ion channel proteins, the alleles C of the HSP-70-1 and G of the HSP-70-2 loci and the haplotype group C-G-T could be considered a diagnostic biomarker in the identification of the LQTS phenotype with a potential to affect the progression and modification of the disease phenotype.

A Common SNP of IL-10 (-1082A/G) is Associated With Increased Risk of Premenopausal Breast Cancer in South Indian Women.

BACKGROUND: Evading the immune destruction and angiogenesis has been the two hallmarks of cancer. Interleukin-10 (IL-10) is a cytokine with immune suppressing (pro-tumorigenic) and anti-angiogenic (anti-tumorigenic) properties, thus making the role of IL-10 in tumorigenesis enigmatic. Previous studies have suggested a critical role of IL10 altered expression in complex process of tumor-microenvironment, co-evolution and tumorigenesis. OBJECTIVES: Evaluating the role of IL10 (-1082A/G) gene promoter polymorphism in breast cancer patients from South India. PATIENTS AND METHODS: A case-control study was conducted with a total of 285 individuals, these include 125 histologically confirmed breast cancer patients and 160 age and sex matched controls. Genotypes were determined by allele-specific polymerase chain reaction (AS-PCR), followed by agarose gel electrophoresis. Statistical analysis was done to test the significance of results obtained. RESULTS: Statistical analysis revealed that AA genotype of the Il-10 -1082A/G polymorphism is significantly associated with breast cancer (AA vs. AG: χ(2) = 14.46, P = 0.0001432, OR = 2.854, 95% CI = 1.68 - 4.849). Up on stratifying subjects based on cancer stage, age at onset, menopausal status, AA genotype has associated with all the sub groups, except for post-menopausal women. There was no significant association which was observed with respected to hormonal status (ER, PR) and Her2/neu status. CONCLUSIONS: The present study suggests that IL-10 AA genotype as a risk factor in the etiology of breast cancer in the South Indian population.

Mutational analysis of SCN5A gene in long QT syndrome.

The SCN5A gene encodes for the INa channel implicated in long QT syndrome type-3 (LQTS-type-3). Clinical symptoms of this type are lethal as most patients had a sudden death during sleep. Screening of SCN5A in South Indian cohort by PCR-SSCP analyses revealed five polymorphisms - A29A (exon-2), H558R (exon-12), E1061E and S1074R (exon-17) and IVS25 + 65G > A (exon-25) respectively. In-silico and statistical analyses were performed on all the polymorphisms. Exon-2 of SCN5A gene revealed A282G polymorphism (rs6599230), resulting in alanine for alanine (A29A) silent substitution in the N-terminus of SCN5A protein. Exon-12 showed A1868G polymorphism (H558R - rs1805124) and its 'AA' genotype and 'A' allele frequency were found to be higher in LQTS patients pointing towards its role in LQTS etiology. Two polymorphisms A3378G (E1061E) and the novel C3417A (S1074R) were identified as compound heterozygotes/genetic compounds in exon-17 of SCN5A located in the DIIS6-DIIIS1 domain of the SCN5A transmembrane protein. IVS25 + 65G > A was identified in intron-25 of SCN5A. The 'G' allele was identified as the risk allele. Variations were identified in in-silico analyses which revealed that these genetic compounds may lead to downstream signaling variations causing aberrations in sodium channel functions leading to prolonged QTc. The compound heterozygotes of SCN5A gene polymorphisms revealed a significant association which may be deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QTc.

Significant Association of Interleukin4 Intron 3 VNTR Polymorphism with Susceptibility to Gastric Cancer in a South Indian Population from Telangana.

BACKGROUND: Gastric cancer (GC) is the fifth most common malignancy and remains a considerable public health burden worldwide. Genetic variations in genes encoding cytokines and their receptors influence the intensity of the Helicobacter pylori associated inflammatory response, which may contribute to individual differences in the outcome and severity of the disease. Interleukin4 is a typical pleiotropic T helper 2 (Th2) cytokine and is a critical mediator of Th1/Th2 balance. It is involved in the regulation of inflammation-mediated carcinogenesis in human organs, including gastric cancer. OBJECTIVE: The present retrospective case control study was undertaken to evaluate the association of IL4 intron 3 VNTR polymorphism with the susceptibility to GC in a south Indian population from Telangana state. MATERIALS AND METHODS: A total of 182 patients with diagnosed GC and 326 randomly selected healthy controls were enrolled in the present study. Genomic DNA was extracted from peripheral leukocytes and genotyping was determined by PCR-based assay. Association between genotypes and gastric cancer was examined by unconditional logistic regression analysis. RESULT: The variant 3R/2R and 2R/2R genotypes of IL4 exon3 VNTR polymorphism had about 1.9 fold and 3fold increased GC risk, respectively, when compared with 3R/3R genotype [3R/2R vs. 3R/3R: adjusted odds ratio (AOR) = 1.90, 95% confidence interval (CI) = 1.23-2.95 P = 0.004 and 2R/2R vs. 3R/3R: AOR (95%CI) = 2.96 (1.29-6.82), P = 0.011]. Furthermore, a significant increased risk of GC was found for the 2R allele carriers (3R/2R + 2R/2R) compared with the 3R/3R genotype (AOR (95%CI) = 2.04 (1.35-3.10), P = <0.000). The IL4 2R allele frequency was 0.28 among the GC group and 0.18 among the controls, and the difference was statistically significant (P = <0.000). CONCLUSION: The present study revealed an association of 2R allele and 2R carrier genotypes in the etiopathogenesis of GC in south Indian population.

Association of endothelial nitric oxide synthase gene T-786C promoter polymorphism with gastric cancer.

AIM: To investigate the role of endothelial nitric oxide synthase -786T > C promoter polymorphism in the etiology of gastric cancer (GC). METHODS: A total of 150 GC patients and 150 control subjects were included in the study. The information on demographic features was elicited with an informed consent from all the patients and control subjects using a structured questionnaire. Helicobacter pylori (H. pylori) infectivity status was tested in antral biopsies from all the subjects by rapid urease test following the method of Vaira et al. Genomic DNA was isolated from whole blood samples following the salting out method of Lahiri et al. Genotype analysis of the rs2070744 polymorphism was carried out by allele-specific polymerase chain reaction method. The genotypes were determined based on the appearance of bands on an agarose gel stained with ethidium bromide under ultraviolet gel documentation with the help of 100 bp ladder. Odds ratios and corresponding 95%CIs were determined using java stat online software. RESULTS: There was a significant difference in the distribution of C allele (C vs T; P = 0.000, OR = 5.038) in patient group compared to the control subjects exhibiting a fivefold increased risk for GC. When the T/T and C/C genotypes were compared, there was an enhanced GC risk for individuals with C/C genotype (T/T vs C/C; P = 0.000). Among the demographic factors, smoking and alcoholism were the common risk factors in patients compared to the control subjects (P < 0.05). Patients with smoking and alcoholism developed cancer even in heterozygous T/C condition (smoking: P = 0.020 and alcoholism: P = 0.005). Individuals with H. pylori infection showed seven fold increased risk for cancer. All the patients with C/C genotype revealed a significant association between H. pylori infection and GC. Among the patients 2.4% of them revealed familial incidence of GC. No significant difference was noticed between cases and controls with regard to consanguinity (P = 0.473). CONCLUSION: The Present data suggest that eNOS-786 C/C genotype and C allele may be considered as potential risk factors in patients with GC.

Role of IL-6 -174(G/C) promoter polymorphism in the etiology of early-onset preeclampsia.

OBJECTIVE: To investigate the relationship between IL-6 -174G/C promoter polymorphism and preeclampsia. METHODS: A total of 140 preeclamptic women and 135 women with normal pregnancy were considered for the present study. A standard amplification refractory mutation system PCR was carried out for genotyping of IL-6 G-174C promoter polymorphism. Genotypic distribution was compared with values predicted by Hardy-Weinberg equilibrium using χ (2) test. Odds ratios and their respective 95 % confidence intervals were used to measure the strength of association. RESULTS: The frequencies observed, CC, GC and GG, were 53.5, 26.6 and 20 % in patients and 26.6, 23.7 and 49.6 % in the controls. There is a significant difference in the distribution of genotypes and alleles of IL-6 G-174 C between the two groups. CONCLUSION: The present study suggests that the IL-6 -174 promoter polymorphism is a major genetic regulator in the etiology of early-onset preeclampsia.

A Rare De Novo Balanced X; 1 Translocation in an Indian Female with Primary Amenorrhea.

BACKGROUND: Translocations involving X chromosome and an autosome are rather rare due to associated infertility in men and subfertility in women. X chromosome translocations are frequently associated with primary or secondary amenorrhea. In this report, a case of primary amenorrhea with a de novo balanced reciprocal translocation was presented between chromosomes X and 1. CASE PRESENTATION: A 24 year-old proposita with the complaint of primary amenorrhea was found to have hypoplastic uterus and streak gonads with a normal hormonal profile. Chromosomal analysis of the proband revealed a de novo translocation of 46, X, t(X; 1) (q21; p32) chromosomal constitution. Parental karyotypes of the proband showed normal karyotype. CONCLUSION: The observed translocation between chromosome X and 1 in the patient suggest either the disruption of a critical gene expression due to position effect or deletion of one or more essential genes in the disrupted long arm of the affected X chromosome. To the best of our knowledge, this is the first report from our ethnic group.

Genotype-phenotype correlation in long QT syndrome families.

Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1-4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of "anticipation" in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.

Role of IL-10 -819(t/c) promoter polymorphism in preeclampsia.

Preeclampsia is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive immune system. Interleukin-10 affects maternal intravascular inflammation, as well as endothelial dysfunction. The aim of the study was to investigate the association between IL-10 T-819 C polymorphism and preeclampsia. A total of 120 pregnant women with preeclampsia and 120 women with normal pregnancy attending the Gynecological Unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the present study. A standard amplification refractory mutation system (ARMS) PCR was carried out for genotyping of IL-10 T-819 C promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups was compared with values predicted by the Hardy-Weinberg equilibrium using χ2 test. Odds ratios (OR) and their respective 95 % confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. The frequencies of IL-10 T-819 C genotypes, CC, CT, and TT, were 47.5, 28.3, and 24.2 % in women with preeclampsia and 20.8, 48.3, and 30.8 % in the controls, respectively. There is a significant difference in the distribution of genotypes and alleles of IL-10 T-819 C between the two groups (test power = 0.66). The present study suggests that the IL-10 T-819 C gene promoter polymorphism can be a major genetic regulator in the etiology of preeclampsia.

Atrial natriuretic peptide gene - a potential biomarker for long QT syndrome.

This study highlights the possible implication of NPPA (natriuretic peptide precursor A) gene in the etiology of Long QT syndrome (LQTS) by population-based as well as familial study. Three SNPs of NPPA - C-664G, C1363A and T1766C were examined by molecular analyses in LQTS, controls and first degree relatives (FDRs). This study revealed a possible association of 1364 C>A SNP 'C' allele with LQTS (p = 0.0013). All three SNPs were in tight linkage disequilibrium. The familial study highlights the association of NPPA SNP with cLQTS and implicating it as a potential biomarker in South Indian population.

Evaluation of Interleukin-10 (G-1082A) Promoter Polymorphism in Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific syndrome that may be life-threatening, especially to the fetus. Several causes have been reported that may have a possible role in the development of the disorder. Interleukin-10 affect maternal intravascular inflammation, as well as endothelial dysfunction. The aim of this study was to investigate the association between IL-10 G-1082A polymorphism and preeclampsia. METHODS: A total of eighty-eight pregnant women with preeclampsia and 100 women with normal pregnancy attending the Gynecological unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the study. A standard amplification refractory mutation system (ARMS) PCR was carried out for genotyping IL-10 G-1082A promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups were compared with values predicted by Hardy-Weinberg equilibrium using χ(2) test. Odd ratios (OR) and their respective 95% confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. RESULTS: The frequencies of IL-10 G-1082A genotypes, GG, GA and AA, were 17.8%, 41.09% and 41.09% in women with preeclampsia and 25%, 28% and 47% in the controls respectively. There was no significant difference in the distribution of genotypes and alleles of IL-10 G-1082A between the two groups (Test power=0.66). CONCLUSION: The present study suggests that the IL-10 G-1082A gene promoter polymorphism is not a major genetic regulator in the etiology of preeclampsia.

Role of tumor necrosis factor-α -308 G/A promoter polymorphism in gastric cancer.

BACKGROUND/AIM: Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancer death world-wide after lung cancer. It is a multifactorial disease with the involvement of both genetic and environmental risk factors. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in severity of outcome of the disease. Tumor necrosis factor alpha (TNF-α) is a potent pro-inflammatory cytokine and acid inhibitor. A bi allelic G to A polymorphism at -308 upstream from the transcription initiation site of the promoter is associated with elevated TNF levels. The present study is aimed at evaluating the role of TNF-α-308 (G → A) gene polymorphism and susceptibility to GC. SUBJECTS AND METHODS: A case-control study was carried out in 114 GC patients and 229 healthy control subjects. TNF-α genotyping at position-308 (G → A) was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method followed by agarose gel electrophoresis. RESULTS: The distribution of TNF-α genotypes at -308 (G → A) were GG 28.07%, GA 66.67% and AA 5.26% in GC patients and GG 33.19%, GA 55.89% and AA 10.92% in control subjects. The frequencies of alleles G and A were 0.614 and 0.386 in GC patients and 0.611 and 0.389 in control subjects respectively. CONCLUSION: The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.

Association of interleukin-10 promoter polymorphism (-1082 g/a) and gastric cancer in andhra pradesh population of South India.

BACKGROUND: Gastric Cancer (GC) is one of the most commonly diagnosed malignancies. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in the outcome and severity of the disease. Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and antiangiogenic functions. Polymorphisms in the IL-10 gene promoter genetically determine inter-individual differences in IL-10 production. In the present study, we investigated the association between the IL-10 -1082 G/A polymorphism and the susceptibility to gastric cancer in a South Indian population from Andhra Pradesh. METHODS: We genotyped 100 patients diagnosed with gastric cancer and 132 healthy control subjects for -1082G/A single nucleotide polymorphism by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) method followed by agarose gel electrophoresis. RESULTS: The distribution of IL-10 genotypes at -1082 G/A were GG 18 %, GA 35% and AA 47 % in gastric cancer patients and GG 31.82 %, GA 37.88 % and AA 30.3% in control subjects. The allelic frequencies of G and A were 0.355 and 0.645 in GC patients and 0.508 and 0.492 in control subjects respectively. The IL-10 -1082 A allele was associated with risk of gastric cancer (OR=1.873, 95%CI-1.285-2.73and P= 0.001048**). CONCLUSION: Our study indicates that allele A of IL-10-1082 G/A polymorphism may be considered as one of the important risk factor in the etiology of gastric cancer.