To systematically investigate the genetic architecture of severe male infertility in Indian men, with a specific focus on chromosomal abnormalities and the contribution of de novo variants. We recruited 247 infertile males between 2021 and 2024 presenting with severe quantitative and qualitative sperm defects. All patients underwent karyotyping and Y chromosome microdeletion STS-PCR. A single molecule molecular inversion probe-based targeted sequencing assay covering 39 male infertility genes was performed in 120 patients, while whole exome sequencing (WES) was conducted in 48 patients using a duo/trio-based approach to enable segregation and de novo variant detection. Gonosomal aneuploidies were observed in 3/247 patients (1.2

BackgroundNiemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal disorder caused by pathogenic variants in NPC1 or NPC2, resulting in impaired intracellular cholesterol trafficking and progressive neurovisceral disease. Although the clinical and molecular spectrum of NPC has been well characterized in several populations, data from India remain limited. The present study aimed to describe the clinical and molecular characteristics of NPC in Indian patients and to expand the mutational spectrum of the disease.MethodsWe conducted a retrospective multicentre study of 28 patients with NPC diagnosed between 2010 and 2026 based on clinical, biochemical, and molecular investigations. Filipin staining was done in two patients. Plasma chitotriosidase activity (n = 21), β-glucosidase (n = 16) and sphingomyelinase activities (n = 21) were measured in plasma sample and leukocytes respectively using fluorometric enzyme assays. Molecular testing included clinical exome sequencing and Sanger sequencing in 2 patients and 1 patient, respectively while single-molecule molecular inversion probes (smMIP)-based targeted sequencing assay was performed in 25 patients. In-silico tools were used to predict the effect of novel variants on protein function and structure.ResultsHepatosplenomegaly was the most common presenting feature, followed by developmental delay, neuroregression, ataxia, seizures, and vertical supranuclear gaze palsy. Importantly, nearly one-third of patients presented with isolated visceral manifestations in the absence of neurological involvement. Molecular analysis identified 32 variants (27 in NPC1 and 5 in NPC2), including 11 novel variants and two exon-level deletions. More than 60% of diagnoses were established during the final four years of the study following implementation of the FRIGE–Sanofi DISHA Program, highlighting the impact of improved access to affordable biochemical and molecular testing for lysosomal storage disorders. The indigenous smMIP assay enabled simultaneous detection of single nucleotide variants, small insertions/deletions, and exon-level copy number variants within a single cost-effective workflow. Structural analysis predicted that novel missense variants affect functionally critical domains of NPC1, resulting in disruption of protein stability, cholesterol trafficking, and lysosomal function.ConclusionThe present study provides a comprehensive characterization of the clinical spectrum and molecular heterogeneity of NPC in a large cohort of patients of Indian origin.

Lysosomal storage disorders (LSDs) are a diverse group of over 70 rare, inherited metabolic conditions that present significant diagnostic and therapeutic challenges, especially in genetically diverse and resource-limited settings like India. To address the lack of a centralized clinical and genomic data registry for LSDs, we established the first government-supported national LSDs biobank in India. This study describes the infrastructure, sample collection, storage procedures, ethical framework, and expected impact of the biobank on research, diagnostics, and patient care. The study includes biological samples and clinical-genetic data from 530 patients, (526 unrelated individuals and 2 sibling pairs), over a 17-year period (2008–2025). Biological samples including genomic DNA from blood, plasma, and urine precipitate were processed for enzyme and genetic investigations. A centralized webpage has been established to manage the biological sample data including clinical, enzyme and genetic data. The LSD biobank cohort encompasses 8 LSD subgroups across 27 disorders, with the most common being Gaucher disease (n = 70), Tay-Sachs disease (n = 62), Mucolipidosis (ML) II/III (n = 44), and Morquio-A (n = 40). Samples originated from 15 Indian states, with a predominance of pediatric cases. Detailed phenotypic, enzymatic, and genomic profiles were generated. Enzyme assays confirmed markedly reduced activity in most cases, with variable residual activity noted in few LSDs. Genetic analyses using Sanger sequencing, PCR-RFLP, targeted gene panel sequencing, and/ or whole exome sequencing detected causative variants. Notably, c.1469T > C in the IDUA gene (29.4

Gaucher disease (GD) is one of the most common lysosomal storage disorders, and has three clinical subtypes (Type 1, 2 and 3). Of the three subtypes, type 2 GD (GD2), also referred to as acute infantile neuronopathic GD is the most severe type. It is characterized by early and profound central nervous system involvement, and patients succumb to disease before two years of age due to severe neurological deterioration and associated complications. It is the rarest of the three subtypes with a reported proportion of < 1

Lynch syndrome (LS) is underdiagnosed in India, particularly outside colorectal cancer (CRC), because pan-cancer data on microsatellite instability (MSI), mismatch repair deficiency (MMRd), and germline predisposition remain limited. We sequentially recruited 519 patients with CRC and extra-colonic cancers from 17 centres in India between 2019 and 2025, and applied a tumour-first approach using MSI testing by PCR-fragment length analysis (PCR-FLA) across all tumours, MMR immunohistochemistry (MMR-IHC) in extra-colonic tumours, BRAF V600E testing in MSI-high CRCs, and germline whole exome sequencing in MSI-high/ BRAF wildtype CRCs and MSI-high/MMRd extra-colonic tumours. MSI-high/MMRd status was identified in 25.6% (133/519) tumours, and 49.6% (66/133) patients harboured pathogenic or likely pathogenic germline variants consistent with LS. CRC showed the highest LS yield, followed by endometrial and ovarian cancers, whereas, several extra-colonic tumour groups showed lower yields, in part reflecting cohort composition and tumour-specific MSI/MMRd prevalence. MLH1 accounted for most LS diagnoses (69.7%, 46/66) followed by MSH2 (18.2%, 12/66). Two recurrent MLH1 variants, c.306G > T and c.156delA, together accounted for 36.4% of all LS cases. Haplotype analysis supported c.156delA as a novel founder variant originating in Gujarat. Concordance between PCR-FLA and MMR-IHC in extracolonic tumours was 93.8%, supporting combined tumour-based screening in pan-cancer workflows. These findings establish the clinical utility of pan-cancer tumour-first LS detection in India and support broader implementation of reflex MSI/MMRd testing, germline confirmation, and cascade testing to improve surveillance, chemoprevention, and risk-reducing management in India.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) play essential roles in neuronal development, synaptic organisation, and signal transduction. Defects in GPI-anchor biosynthesis and remodelling cause rare multisystem neurodevelopmental disorders, among which post-GPI attachment to proteins 1 (PGAP1) deficiency is particularly uncommon. PGAP1 encodes an inositol deacylase that removes an acyl chain from the inositol ring of the GPI anchor, an early remodelling step required for proper trafficking and membrane localisation of GPI-APs. Loss of PGAP1 function leads to structurally abnormal GPI-APs and impaired cellular processes. Fewer than 40 affected individuals have been described, limiting understanding of the clinical spectrum. We systematically characterised 15 individuals with PGAP1 deficiency from 11 unrelated families across 11 countries using standardised phenotyping, molecular analysis, and functional assays. Eight previously unreported pathogenic variants were identified across six exons, including splice-site, truncating, and missense variants, with exon 2 containing the largest cluster. Individuals ranged from 8 months to 23 years. Intellectual disability and global motor delay were the most common features (93.3%), and only 40.0% achieved independent ambulation. Seizures occurred in 66.7% of cases. Scoliosis was observed in 40.0%, and peripheral neuropathy in 33.3%, the latter representing an under-recognised aspect of the disorder. Functional studies showed resistance to phosphatidylinositol-specific phospholipase C cleavage of GPI-APs, confirming impaired GPI-anchor remodelling. These findings expand the genotypic and phenotypic landscape of PGAP1 deficiency, highlight neuropathy as part of the disease spectrum, and emphasise the need for genetic testing and functional validation for accurate diagnosis and management.

Rare genetic disorders are increasingly diagnosed due to advancing genetic technology, whilst, treatment for them is challenging. Therefore, their prevention by prenatal diagnosis is a way forward to reduce the overall burden. The present study provides an overview of a cohort of patients who were offered prenatal diagnosis for genetic disorders at a tertiary genetic center in India. The study included 1,738 prenatal samples for the period of 2008 to 2022, identified as being at high risk for rare genetic disorders based on family history, previous affected children, and abnormal ultrasound findings. Participants underwent prenatal diagnostic tests, including chorionic villus sampling or amniocentesis, or fetal blood by various molecular techniques and enzyme-based studies. Data regarding patient demographics, types of disorders screened, and diagnostic outcomes were collected and analyzed. Of the 1738 cases, 467 (26.87

Chronic mask use in healthcare professionals might influence change in genetic composition of hypoxia inducible factor-1α (HIF-1α) gene. The study determined the genetic make of HIF-1α gene and determined the association of variants with serum HIF-1α levels and metabolic effects in individuals using masks. The study was conducted on thirty healthy health professionals using masks and twenty not using masks. Serum HIF-1α was measured using ELISA and gene sequencing done for HIF-1α gene. 28 CTRI Number: CTRI/2023/06/054233 [Registered on 21/06/2023].

Despite having heritability estimates of 80

Autism has been lately regarded as a synaptopathy due to growing genetic and experimental evidence that suggests associated genes to converge at the synaptic pathway. Several genes implicated in autism encode synaptic adhesion molecules and contain leucine rich repeats suggesting their role in synapse formation. This case report highlights LRFN1 gene as a potentially novel candidate associated with autism. The LRFN1 protein is a synaptic adhesion like molecule that contains leucine rich repeats. It has direct interaction with the post-synaptic density 95 protein, a predominant protein involved in synaptic function which has previously been associated with autism. A two year and three months old male proband diagnosed with non-syndromic autism spectrum disorder as per the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria was evaluated for a genetic aetiology. Karyotyping and chromosomal microarray did not reveal any quantitative genomic imbalances. Whole exome sequencing revealed a heterozygous variant c.176T > C (p.Val59Ala) in exon 1 of the LRFN1 gene. Segregation analysis in parents by Sanger sequencing showed the variant to be de novo in origin. Together with in silico analyses, the variant as well as the gene is likely to have a damaging effect leading to autism phenotype in the present case. This case reports LRFN1 gene as a potential novel candidate that could be associated with ASD through the synaptic pathway. Possible modes of action have been hypothesized taking into account its direct interaction with the post-synaptic density 95 protein and associated protein complex.

Non-immune hydrops fetalis (NIHF) could result from several hematological and metabolic disorders, including alpha thalassemia, some mucopolysaccharidoses (MPSs), such as MPS I, MPS VII, and Gaucher disease; as well as some lethal skeletal dysplasias and RASopathies [1–4]. Early-onset sialidosis or the infantile form is a severe disorder that is usually fatal during infancy if untreated. We report the clinical course of an infant with antenatally detected hydrops, in whom novel compound heterozygous variants were identified in the NEU1 gene.

Abstract Background Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late‐infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult‐onset retinal dystrophy. Classic late‐infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non‐syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. Methods Here we present longitudinal studies on four adult‐onset patients who were biallelic for four MFSD8 variants. Results Two unrelated patients who presented with adult‐onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. Conclusions Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8‐related disease, adult‐onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.

Abstract Background Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. Conclusion The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Lysosomal storage disorders (LSDs) in adults have milder phenotype and variable age at presentation. Several studies have described the phenotype, genotype and treatment outcomes for adult-onset LSDs like Gaucher, Fabry, Pompe disease and others. We describe the first systematic study on the occurrence of LSDs in an adult population from India. It describes, the key clinical signs seen in these patients and those from literature review that can aid in early detection. Of 2102 biochemically diagnosed LSDs cases, 32 adult patients were identified with LSDs. Based on the clinical suspicion, screening test and enzyme study was carried out. Twenty-two patients were subjected to a genetic study to identify the causative variant in a respective gene. Of the 32 adult patients, we observed a maximum percentage of 37.5% (n = 12) cases with Gaucher disease, followed by 13% (n = 4) with Fabry disease. We found 10% of cases with MPS IVA and MPS I, and 9% cases with Pompe. Single case of adult mucolipidosis III and two cases each of Type 1 Sialidosis, Niemann-Pick disease B and metachromatic leukodystrophy were identified. We observed two common variants p.Leu483Pro and p.Ala487Thr in the GBA1 gene in 23% of Indian patients with adult Gaucher disease. No common variants were observed in other aforementioned LSDs. Study identified 50% of Fabry patients and 4% of Gaucher patients diagnosed at our centre to be adults. The prevalence of adult Pompe patients was low (3.4%) as compared to 80% reported in the Caucasian population. Adult LSDs such as, MPS III, GM1/GM2 gangliosidosis and Krabbe disease were not identified in our cohort.

Abstract Background Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India. Results 903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood. Conclusion We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

We aimed to describe the clinical and genetic characteristics of 16 individuals with KBG syndrome (KBGS) from 13 Indian families. We retrospectively analyzed the clinical details of individuals with KBGS harboring a likely pathogenic/pathogenic variant in ANKRD11. We also analyzed their facial gestalt using Face2Gene and recorded the top three differential disorders suggested by the application. The most frequent clinical features observed in our cohort were as follows: learning and intellectual disability-14/15 (93%), skeletal abnormalities-14/15 (93%), postnatal short stature-13/15 (87%), brachydactyly-11/15 (73%), and characteristic facial appearance-13/15 (87%). We identified 12 single nucleotide variants (SNVs), including six recurrent and six novel variants, and a copy number variant in the 16q24.3 region encompassing ANKRD11 gene. The novel variants were as follows: p.(Gln1236Ter), p.(Asp884ThrfsTer93), p.(Arg1466GlyfsTer87), p.(Tyr2056Ter), p.(Leu955TrpfsTer22), and p.(Lys766ArgfsTer10). The identified SNVs in ANKRD11 clustered around exon 9. We observed a high concordance of Face2Gene in predicting KBGS.

Complex chromosomal rearrangements (CCRs) often remain unidentified as they are rarely observed in the general population. Females with CCRs are generally recognized on the identification of an affected child with multiple congenital anomalies (MCA) or having a history of repeated pregnancy loss/bad obstetric history (RPL/BOH). In contrast, males with CCRs are diagnosed primarily due to infertility. This study aimed to carry out a systematic epidemiological analysis of CCRs in one of the largest series from the Indian population. In addition, a review of the literature on female CCR carriers experiencing RPL/BOH has been compiled in an attempt to identify the genomic landscape of breakpoints, commonly involved chromosomes, and the breakpoint regions. A total of 8560 healthy individuals with normal physical and mental well-being and had no history of any obvious genetic disorder at the time of presentation were referred for chromosome analysis in view of RPL/BOH between 1994 and 2024. Of them, 8158 had a normal chromosome complement whereas, 402 (4.7

SCY1-like protein 2 (SCYL2) is a member of the SCY1-like pseudokinase family which regulates secretory protein trafficking. It plays a crucial role in the nervous system by suppressing excitotoxicity in the developing brain. Scyl2 knockout mice have excess prenatal mortality and survivors show severe neurological dysfunction. Bi-allelic loss-of-function (LOF) variants in SCYL2 were recently associated with arthrogryposis multiplex congenita-4 (AMC4) following the report of 6 individuals from two consanguineous unrelated families. The AMC4 phenotype described included severe arthrogryposis, corpus callosum agenesis, epilepsy and frequently, early death. We describe here two additional similarly affected individuals with AMC4, including one diagnosed in the prenatal period, with bi-allelic LOF variants in SCYL2, and two individuals homozygous for missense variants in the protein kinase domain of SCYL2 and presenting with developmental delay only. Our study confirms the association of SCYL2 with AMC4 and suggests a milder phenotype can occur, extending the phenotypic spectrum of autosomal recessive SCYL2-related disorders.