Mohd Fareed

Objective The study aimed to evaluate the association of UCP2 gene polymorphism − 866 G/A and its expression with diabetes predisposition in the North Indian population. Methods The study involved 850 subjects, including 425 each T2DM and control subjects. The serum metabolic and clinical parameters were estimated using standard protocols. The PCR–RFLP based genotyping was performed to determine UCP2 gene polymorphism, while the expression was measured by real-time quantitative PCR. Results The genotypic and allelic frequencies showed a significant difference in cases compared to controls (p < 0.05). The diabetes patients had a 4.2-fold decrease in UCP2 gene expression. The expression was 29.8 and 8.4 fold lower in diabetes patients with homozygous (AA) and heterozygous (GA) mutation at − 866 locus of UCP2 nucleotide sequence, respectively. When categorized according to age and BMI, the T2DM subjects with age ≥ 50 and BMI ≥ 25 had a 5.53 and 8.2-fold decrease in UCP2 expression, respectively. The diabetes subjects with homozygous and heterozygous mutation demonstrated a pathological increase in serum metabolic and clinical parameters, which corroborated with UCP2 gene expression, indicating a strong association between the two. Intriguingly, we did not find any association between − 866 G/A polymorphism of UCP2 with serum insulin levels. Conclusion Our investigation is the first among the studies conducted in Jammu and Kashmir to work on adipose tissue and UCP2 gene polymorphism. The association of − 866 G/A SNP of the UCP2 gene with its expression in diabetes patients appears to be an important genetic determinant in the progression of T2DM. Moreover, age ≥ 50 years and BMI ≥ 25 could be considered risk factors for developing T2DM in the studied population.

Objective: The objective of the study was to evaluate the association of UCP2 gene polymorphism -866 G/A and its expression with diabetic predisposition in North Indian population. Methods: The study involved 850 subjects, including 425 each T2DM and control subjects. The serum metabolic and clinical parameters were estimated using standard protocols. The genotyping for determining UCP2 gene polymorphism was performed by the PCR-RFLP while the expression was measured by real-time quantitative PCR. Results: The genotypic and allelic frequencies showed a significant difference in cases when compared to controls (pUCP2 gene expression. The expression was 29.8 and 8.4 fold lower in diabetic patients with homozygous (AA) and heterozygous (GA) mutation at -866 locus of UCP2 nucleotide sequence respectively. When categorized according to age and BMI, the T2DM subjects with age ≥50 and BMI ≥25 had 5.53 and 8.2-fold decrease in UCP2 expression. The diabetic subjects with homozygous and heterozygous mutation demonstrated a pathological increase in serum metabolic and clinical parameters which again corroborated with UCP2 gene expression indicating a strong association between the two. Intriguingly, we did not find any association between -866 G/A polymorphism of UCP2 with serum insulin levels. Conclusion: The association of -866 G/A SNP of UCP2 gene with its expression in diabetic patients appears to be an important genetic determinant in the progression of T2DM. Moreover, Age ≥50 years and BMI ≥25 could be considered as a risk factor for developing T2DM in the studied population.

Nephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

Non-syndromic hearing loss (NSHL) is one of the most frequent auditory deficits in humans characterized by high clinical and genetic heterogeneity. Very few studies have reported the relationship between OTOF (Locus: DFNB9) and hereditary hearing loss in India. We aimed to decipher the genetic cause of prelingual NSHL in a large affected Muslim consanguineous families using whole-exome sequencing (WES). The study was performed following the guidelines and regulations of the Indian Council of Medical Research (ICMR), New Delhi. The population was identified from Jammu and Kashmir, the Northernmost part of India. Near about 100 individuals were born deaf-mute in the village of 3,000 inhabitants. A total of 103 individuals (with 52 cases and 51 controls) agreed to participate in this study. Our study revealed a rare non-sense homozygous mutation NC_000002.11:g.2:26702224G>A; NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708^∗) in the 18th exon of the OTOF gene. Our study provides the first insight into this homozygous condition, which has not been previously reported in ExAC, 1,000 Genome and genomAD databases. Furthermore, the variant was confirmed in the population cohort (n = 103) using Sanger sequencing. In addition to the pathogenic OTOF variant, the WES data also revealed novel and recurrent mutations in CDH23, GJB2, MYO15A, OTOG, and SLC26A4 genes. The rare pathogenic and the novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions SCV001448680.1, SCV001448682.1 and SCV001448681.1. We conclude that OTOF-related NSHL hearing loss is prevalent in the region due to successive inbreeding in its generations. We recommend premarital genetic testing and genetic counseling strategies to minimize and control the disease risk in future generations.

Context: Inbreeding increases the level of homozygotes for autosomal recessive disorders and is the major objective in clinical studies. The prevalence of consanguinity and the degree of inbreeding vary from one population to another depending on ethnicity, religion, culture and geography. Global epidemiological studies have revealed that consanguineous unions have been significantly associated with increased susceptibility to various forms of inherited diseases. Objective: The study aimed to determine the role of consanguinity in human health and to highlight the associated risks for various diseases or disorders. Methods: PubMed and Google Scholar search engines were used to explore the published literature on consanguinity and its associated risks using the key words “consanguinity”, “prevalence”, “inbreeding depression”, “coefficient of inbreeding”, “child health”, “mortality”, “human health”, “homozygosity” and “complex diseases” in different combinations. The studies were screened for eligibility on the basis of their epidemiological relevance. Results: This comprehensive assessment highlights the deleterious consequences in populations with a higher prevalence of consanguinity among different countries worldwide. Conclusions: To avoid the inbreeding load there is the need to improve socioeconomic and educational status and to increase public awareness of reproductive health and anticipated deleterious effects. Pre-marital and pre-conception counselling of consanguineous populations should be an integral part of health policy to train people and make people aware of its harmful consequences. Furthermore, runs of homozygosity (ROH) and whole-exome sequencing (WES) are useful tools in exploring new genomic signatures for the cause of inbreeding depression.

Cognitive ability tests are widely assumed to measure maximal intellectual performance and predictive associations between intelligence quotient (IQ) scores and later mental health problems. Very few epidemiologic studies have been done to demonstrate the relationship between familial inbreeding and modest cognitive impairments in children. We aimed to estimate the effect of inbreeding on children’s cognitive behavior in comparison with non-inbred children. A cohort of 408 children (6 to 15 years of age) was selected from inbred and non-inbred families of five Muslim populations of Jammu region. The Wechsler Intelligence Scales for Children (WISC) was used to measure the verbal IQ (VIQ), performance IQ (PIQ) and full scale IQ (FSIQ). Family pedigrees were drawn to access the family history and children’s inbred status in terms of coefficient of inbreeding (F). We found significant decline in child cognitive abilities due to inbreeding and high frequency of mental retardation among offspring from inbred families. The mean differences (95% C.I.) were reported for the VIQ, being −22.00 (−24.82, −19.17), PIQ −26.92 (−29.96, −23.87) and FSIQ −24.47 (−27.35, −21.59) for inbred as compared to non-inbred children (p>0.001). The higher risk of being mentally retarded was found to be more obvious among inbred categories corresponding to the degree of inbreeding and the same accounts least for non-inbred children (p2 = 0.436), PIQ (R² = 0.468) and FSIQ (R² = 0.464) with increasing inbreeding coefficients (p<0.01). Our comprehensive assessment provides the evidence for inbreeding depression on cognitive abilities among children.