SciGenom Labs (India)

To identify genomic risk factors for diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), in South Indians. Phenotyping, including optical coherence tomography (OCT), of South Indians (n = 2538) with type 2 diabetes (T2D) was obtained. Genome-wide association studies (GWAS) were performed for DR, PDR, and DME with covariate adjustment. The results were replicated in two cohorts. T2D polygenic risk scores (PRS) were examined to determine if DR cases were enriched for T2D loci. A novel locus on chromosome 10 [rs11199996 (OR = 4.10, P = 2.88 × 10–8)] was associated with PDR, replicated in other cohorts, and is located near genes involved in retinal light transduction and growth hormone signaling. Several near genome-wide significant loci were identified, including rs76323047 in the glucokinase gene (GCK, P = 3.89 × 10–7), a glucose sensor; this risk variant displays higher frequency in Asian populations. T2D PRS showed consistent associations with DR, particularly PDR, suggesting that DR cases have a higher genetic load for T2D. This first DR GWAS in South Indians identified a significant association between a chromosome 10 variant and PDR. We also found notable associations of T2D PRS with DR.

ABSTRACT Background and Aim MASLD affects 30–38% of Indian adults, yet the contribution of genetic risk variants to disease susceptibility and fibrosis progression remains poorly characterised. We investigated the association of 12 candidate SNPs with MASLD susceptibility and fibrosis severity in North Indian patients, benchmarking allele frequencies against IndiGenomes and global populations. Methods Sixty-nine MASLD patients (75.4% male; median BMI 29.8 kg/m²) from a tertiary care liver clinic in New Delhi were genotyped for 12 SNPs using Illumina custom BeadChip array and Sanger sequencing. Patients were stratified by liver stiffness measurement (LSM): significant fibrosis (≥8 kPa, n=38) versus no significant fibrosis (<8 kPa, n=31). Allele frequencies were compared with IndiGenomes (∼1,020 Indian individuals) and 1000 Genomes populations. Results PNPLA3 rs738409 G allele was the strongest within-cohort predictor of significant fibrosis (allelic OR 2.89, 95% CI 1.35–6.19, P=0.006; dominant model OR 3.94, P=0.008), with carriers demonstrating higher LSM (median 15.6 vs. 7.5 kPa, P=0.005). SAMM50 rs3761472 (OR 2.12, P=0.065) and FTO rs9939609 (OR 2.08, P=0.089) showed non-significant trends. In the population-level comparison, APOC3 rs2854116 T allele was the only variant significantly enriched after Bonferroni correction (64.0% vs. 47.9%; OR 1.93, 95% CI 1.35–2.77, P<0.001), followed by PNPLA3 (33.3% vs. 24.1%, OR 1.57, P=0.019) and SAMM50 (31.2% vs. 22.6%, OR 1.55, P=0.028). Notably, APOC3 showed no association with fibrosis (OR 0.96, P=1.000), suggesting a role in susceptibility rather than progression. All SNPs were in Hardy-Weinberg equilibrium. Conclusions This study reveals a dissociation between genetic determinants of MASLD susceptibility and fibrosis progression in North Indian patients. APOC3 rs2854116 predisposes to MASLD at the population level, while PNPLA3 rs738409 drives fibrosis severity within established disease, underscoring the need for ancestry-specific genetic risk stratification. Graphical Abstract

Neurological health score (NHS), indicating the health of brain and nervous system, helps in identifying high risk individuals, and in recommending lifestyle modifications. In the present study, we developed NHS based on genetic, lifestyle and biochemical variables associated with eight neurological disorders - dementia, stroke, Parkinsons disease, amyotrophic lateral sclerosis, schizophrenia, bipolar disorder, multiple sclerosis and migraine. UK Biobank data from Caucasian individuals was used to develop the model, and the data from individuals of Indian ethnicity was used to validate the model. Logistic regression and XGBoost algorithms were used in selecting the significant variables for the disorders. NHS developed from the selected variables was found to be very significant after adjusting for age and sex (AUC:0.6, OR: 0.95). Higher NHS was associated with a lower risk of neurological disorders and better social well-being. Highest NHS group (top 25%) showed 1.3 times lower risk compared to the rest of the individuals. Results of our study help in developing a framework for quantifying the neurological health in clinical setting.

Isolated growth hormone deficiency (IGHD) is one of the treatable causes of short stature. We aimed to describe the clinical, biochemical, and molecular characteristics of IGHD and identify clinical predictors of mutation positivity and first-year height response to recombinant human growth hormone (rhGH). Sixty-three children with IGHD who were on a minimum of one year of rhGH therapy were included. Detailed auxology, growth hormone provocative testing, and pituitary MRI were performed. Genetic variants were identified by whole-exome sequencing and correlated with auxological and biochemical parameters. The first-year height response was assessed as ΔHeight SDS, and predictors of response were analysed using regression models. The mean age at presentation was 8.9 ± 2.9 years; 57% were born to consanguineous parents. Severe auxological impairment was observed, with a mean height SDS of - 4.29 ± 1.09, and a mean genetic height deficit of - 2.42 ± 1.12 SDS. Genetic variants were identified in 49% of the cohort, predominantly in GHRHR (39.7%), with the p.Glu72Ter being the most frequent, while GH1 variants were less prevalent (4.8%). Genetic variant-positive children presented at a younger age, with more severe growth failure, and a better response to rhGH therapy. Regression analysis identified genetic variant-positive status as an independent predictor of favourable first-year growth response (ΔHeight-SDS:1.24 ± 0.50). The South Indian IGHD cohort exhibits a distinct genetic profile, with GHRHR p.Glu72Ter being the most frequent variant, consistent with a founder effect. Severe short stature, low peak stimulated growth hormone levels, and superior first-year growth response indirectly predicted mutation positivity.

[This corrects the article DOI: 10.3389/fgene.2025.1603542.].

Hypophosphatasia (HPP) is a rare disorder, with only two genetically proven cases reported from India. Here, We report five Indian patients with genetically proven hypophosphatasia and describe their clinical, biochemical, and genetic profiles. The study included patients with genetically proven hypophosphatasia managed at different healthcare centers in South India. The participants' case records were reviewed, and relevant phenotypic and genotypic information was collected and analyzed. Case 1 presented at 4 months of age for failure to thrive, found to have persistent hypercalcemia for which she received bisphosphonate therapy. A low alkaline phosphatase was recognized later. Case 2 presented during adolescence with bilateral genu valgus and delayed dentition with classical tongue-like translucencies on radiology and low alkaline phosphatase. Genetic evaluation in cases 1 and 2 revealed compound heterozygous variants in the ALPL gene. Case 1 received asfotase alfa with remarkable improvement in growth. Case 3 presented with multiple vertebral fractures at 33 years of age whereas cases 4 (42 years) and 5 (63 years) presented with musculoskeletal pains with delayed diagnosis for 8 and 13 years, respectively. Cases 3-5 had heterozygous variants in the ALPL gene. In the largest case series of hypophosphatasia from India, we report five cases of hypophosphatasia with two novel variants. Our study emphasizes the need to increase awareness regarding the disease to improve its early diagnosis and also, the need to form strategies to reduce the challenges in obtaining enzyme replacement therapy for hypophosphatasia in India.

Abstract Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have either arisen de novo in different families due to mutation hotspots or are inherited from a common ancestor (founder) that lived several generations back. Testing for founder variants can facilitate molecular diagnosis of LS more efficiently and cost effectively than screening for all possible variants in the MMR genes. Here, we report a study of the missense variant c.306G>T in the MLH1 gene, the first potential founder variant identified in LS patients of Indian ethnicity. Haplotype analysis consisting of 25 LS carriers with the MLH1 c.306G>T variant and 100 healthy controls confirmed a shared haplotype in cases spanning a 27.8kb region encompassing the c.306G>T variant (𝝌2 =96.418; p=<0.0001). Age of variant analysis suggests the variant to have arisen in the population approximately 800 years (95% CI: 670-934 years) ago. Furthermore, it is estimated that c.306G>T variant is likely to be observed in 6.4% of all LS patients of Indian ethnicity. These findings have important implications for genetic counselling and molecular diagnosis of Lynch syndrome.