Objective: Posterior fossa anomalies (PFAs) encompass a spectrum of central nervous system malformations affecting the cerebellum, brainstem, and surrounding cerebrospinal fluid spaces. This study evaluates the prenatal diagnosis, genetic findings, and pregnancy outcomes of PFAs in a tertiary care setting in India. Methods: A retrospective analysis was conducted on 35 cases of PFAs diagnosed via prenatal ultrasound and fetal MRI between January 2023 and May 2024. Anomalies were classified based on standard criteria, and genetic testing (karyotypte, chromosomal microarray analysis and whole exome sequencing) was offered. Pregnancy outcomes, including termination, live birth, and neonatal survival, were documented, with short-term neurodevelopmental follow-up conducted via telephonic inquiries. Results: The most common PFAs identified were Vermian Agenesis/Hypoplasia (VA/VH) and Cerebellar Hypoplasia (CH), each accounting for 25.71% of cases, followed by Dandy-Walker Malformation (20%). Isolated PFAs were observed in 37.14% of cases, while 62.85% had additional anomalies. Genetic testing was performed in 74.2% of cases, revealing variants in 5.71%. Karyotyping was performed in all tested cases and yielded normal results, while additional molecular testing with chromosomal microarray analysis (5 cases) and whole-exome sequencing (3 cases) detected clinically relevant variants in selected fetuses with posterior fossa anomalies. Among the 35 pregnancies, 65.71% opted for termination, facilitated by the Medical Termination of Pregnancy (MTP) Act, particularly for cases diagnosed beyond 24 weeks of gestation. Of the 9 live births, 2 neonates with vermian hypoplasia (5.71%) died within one month, while 6 (17.14%) had normal developmental milestones at 6 months including 6 babies with mega cisterna magna and one with an arachnoid cyst. One infant exhibited delayed milestones. Conclusion: PFAs present with diverse prognostic implications, necessitating detailed imaging, genetic evaluation, and individualized counseling. The MTP Amendment Act, played a crucial role in providing extended access to termination in pregnancies with severe PFAs and poor prognoses.

Prenatal diagnosis (PND) is an effective measure to prevent births with transfusion-dependent β-thalassemia (TDT) and other severe hemoglobinopathies. However, multicentric consolidated data from high-volume Indian referral laboratories is limited. The authors collated a multi-center experience of invasive PND for β-thalassemia and the major hemoglobinopathies, including center-wise volumes, affected-fetus rates, trends in primigravida referrals, and diagnostic challenges from seven Indian tertiary-care referral centers with a minimum of 10 y PND services. Retrospective data were contributed by SGRH-New Delhi, ICMR-NIIH-Mumbai, PGIMER-Chandigarh, AIIMS-New Delhi, NIMS-CDFD-Hyderabad, CMC-Vellore and SGPGI-Lucknow. Carrier evaluation was based on blood counts and Hb-HPLC. Fetal diagnosis utilized chorionic villus sampling or amniocentesis with molecular testing by ARMS-PCR, reverse dot-blot and/or Sanger sequencing as per local practices. Descriptive analyses summarized volumes, proportions of fetuses with biallelic HBB variants, and primigravida referral trends. Across centers, 6,780 PND procedures were performed over 2015–2024, with ICMR-NIIH and SGRH contributing 58.2

Multiomics, next-generation, and long-read sequencing approaches have transformed the practice of medical genetics. Complex cases often require several person-hours to make sense of the tens of thousands to millions of variants and biochemical patterns in each patient. Availability of massive datasets challenges traditional analytical and interpretive approaches. Artificial intelligence offers powerful ways to handle the growing volume and complexity of genomic and phenotypic data in clinical genetics. It is already influencing several areas of practice, including variant prioritization and interpretation, rare disease screening, and aspects of precision medicine. However, translating these advances into routine clinical use has proven difficult due to the underrepresentation of various populations, ethical issues, and issues related to data governance. As the majority of these tools are used in isolation, separate from hospital information systems and routine reporting pipelines, they are not optimally utilized. With continued progress in precision medicine and genomics, these AI genomic tools are likely to be integrated more into medical genetics practice, rather than remaining restricted to specialised or experimental settings.

BACKGROUND:Delayed platelet recovery remains a frequent and clinically significant complication following hematopoietic stem cell transplantation (HSCT) in children, contributing to increased transfusion burden, bleeding risk, and prolonged hospitalization. Thrombopoietin receptor agonists (TPO-RAs), including romiplostim, have demonstrated activity in post-transplant thrombocytopenia; however, prospective pediatric data on their early post-transplant use are limited. We evaluated the safety and potential effects of early romiplostim administration on platelet and hematopoietic recovery following pediatric HSCT. METHODS:In this prospective, open-label, randomized pilot study conducted at a tertiary care center in India, children aged 1-18 years undergoing autologous or allogeneic HSCT were randomized (1:1) to receive standard post-transplant care with or without romiplostim. Romiplostim (5 µg/kg subcutaneously) was administered on Days +1 and +8 post-transplant (or Days +5 and +12 for haploidentical transplants with post-transplant cyclophosphamide). The primary endpoint was time to platelet engraftment (platelet count ≥20 × 109/L for 3 consecutive days without transfusion). Secondary endpoints included platelet transfusion requirements, platelet nadir, platelet counts on Day +28, time to platelet count ≥50 × 109/L, neutrophil recovery, bleeding, and thrombotic events. RESULTS:Thirty-two children were enrolled (romiplostim n = 17; control n = 15). Median time to platelet engraftment was comparable between the romiplostim and control groups (12 vs. 12.5 days; p = 0.88), with no significant difference on Kaplan-Meier analysis. Platelet transfusion requirements, platelet nadir, and time to platelet count ≥50 × 109/L were also similar between groups. By Day +28, higher platelet counts were observed in the romiplostim arm, with exploratory subgroup analysis demonstrating higher platelet counts following allogeneic HSCT. Romiplostim recipients also demonstrated higher absolute neutrophil counts on Day +28. No thrombotic events, severe bleeding episodes, or drug-related serious adverse events were observed. CONCLUSION:Early administration of romiplostim following pediatric HSCT was safe and well tolerated, with no significant treatment-related toxicity observed. Although it did not shorten time to platelet engraftment, exploratory analyses demonstrated higher Day +28 platelet and neutrophil counts, generating the hypothesis that romiplostim may support sustained hematopoietic recovery. These findings require confirmation in larger, adequately powered multicenter studies before conclusions regarding efficacy can be drawn.

Down syndrome (DS) is the most common chromosomal abnormality associated with intellectual disabilities. Many metabolic issues begin in childhood, and children without DS are reported to have a high prevalence of metabolic syndrome (MS) according to various studies. However, our understanding of the risk of MS in children with DS is limited. A cross-sectional study assessed the prevalence of MS in DS children aged 10-18 during 2022-2024. Demographic details and anthropometric measurements were recorded for all participants. Fasting blood samples were collected for blood glucose, insulin, and lipid profile analysis. The modified NCEP-ATP III criteria were used to classify the MS. We also evaluated insulin resistance (IR) using HOMA-IR and body adiposity patterns with a DEXA scan in DS children aged 6-18. Seventy-six children aged 10-18 and 38 aged 6-9 were enrolled. The prevalence of MS was 18% in our cohort. Dyslipidemia (high triglycerides and low HDL) was observed in 21% and 15.8% of children aged 6-9 and 10-18, respectively. IR was observed in 27.6% and 7.8% of children aged 10-18 and 6-9, respectively. IR was positively correlated with BMI, whereas no correlation was observed with MS or dyslipidemia. Total body fat mass was positively correlated with MS. Our study observed a higher prevalence (18.0%) of MS than age-matched general population studies (pooled prevalence: 5.0%). Additionally, we observed a high prevalence of dyslipidemia and IR from 6 years of age. The results indicate the need to review the management guidelines and consider incorporating metabolic workups.

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

OBJECTIVES:To evaluate the short- and long-term clinical and laboratory outcomes of Enzyme Replacement Therapy (ERT) in Indian patients with Gaucher disease (GD) and to identify factors influencing the therapeutic response. METHODS:This retrospective, multicentre cohort study included 204 patients with confirmed GD across 13 Indian centres. Eligible participants had received at least one year of ERT and provided both baseline and follow-up data. Patients were stratified by splenectomy status. Longitudinal outcomes assessed over 1-5, 10, and 15 y included hemoglobin levels, platelet counts, liver and spleen volumes, chitotriosidase activity, bone pain, bone mineral density (BMD), and height/weight Z-scores. Subgroup analyses evaluated the impact of age at ERT initiation, GD subtype, genotype, and baseline disease severity. RESULTS:Of the 204 patients, 173 were non-splenectomised and 31 were post-splenectomy; notably, 136 (66.7%) presented with the GD3 phenotype. The median age at symptom onset, diagnosis, and ERT initiation was 1.5 y, 2.6 y, and 4.3 y respectively. The p.L483P allele was the predominant variant in the cohort. Within the first 1-5 y of ERT, non-splenectomised patients demonstrated marked improvements in hematological parameters, organomegaly, biomarker activity, growth metrics, and bone pain. These improvements were sustained through 10-15 y, characterized by stabilized visceral parameters, persistently low biomarker levels, steady growth, and a low incidence of new skeletal complications. Early initiation of ERT was associated with a greater magnitude of hematological response as early as 1 y. CONCLUSIONS:ERT facilitates rapid clinical and laboratory improvements within 1-5 y, with benefits sustained over 10-15 y in Indian GD patients. Despite significant diagnostic delays and the advanced stage of disease at presentation common in this population, long-term outcomes remain highly favourable. Early initiation of ERT is critical for optimizing treatment response and preventing irreversible sequelae.

Neurofibromatosis type 1 (NF1) is a complex multisystem disorder with marked phenotypic heterogeneity and variable expressivity. While its clinical features have been extensively documented in Western populations, data from India remain limited and largely based on smaller cohorts. This study provides a comprehensive description of the NF1 phenotype in an Indian cohort of 72 patients. The study also explored the frequency of NF1 deletions/duplications in NF1 and their contribution to clinical variability. This cohort adds to the limited Indian data on NF1 and highlights the need for molecular testing in routine clinical evaluation. These findings emphasize the importance of region-specific phenotypic profiling and support the integration of genetic insights into individualized patient care.

BACKGROUND: Megalencephalic Leukoencephalopathy with subcortical cysts (MLC), a rare and progressive neurodegenerative disorder involving the white matter, is not adequately recapitulated by current disease models. Somatic cell reprogramming, along with advancements in genome engineering, will allow the establishment of in-vitro human models of MLC for disease modeling and drug screening. In this study, we utilized cellular reprogramming and gene-editing techniques to develop induced Pluripotent Stem Cell (iPSC) models of MLC to recapitulate the cellular context of the classical MLC-impacted nervous system. RESULTS: MLC iPSCs were comprehensively characterized for pluripotency and were subsequently differentiated to disease-relevant cell types: Neural Stem Cells (NSCs) and astrocytes. RNA (Ribonucleic acid) sequencing profiling of MLC NSCs revealed a set of differentially expressed genes related to neurological disorders and epilepsy, a common clinical finding within MLC disease. This gene set can serve as a target for drug screening for the development of a potential therapeutic for this disease. Upon differentiation to the more disease relevant cell type- astrocytes, MLC-characteristic vacuoles were clearly observed, which were distinctly absent from controls. This emergence recapitulated a distinguishing phenotypic marker of the disease. CONCLUSIONS: Through the creation and analyses of iPSC models of MLC, our work addresses a critical lacunae in the field- relevant cellular models of MLC for use in both disease modeling and drug screening assays. Further investigation can utilize these MLC iPSC models, as well as generated transcriptomic data sets and analyses, to identify potential therapeutic interventions for this debilitating disease.

India bears a high burden of thalassemia, underscoring the need for enhanced awareness, systematic screening, and standardized, high-quality care. In the absence of indigenous guidelines, gaps remain in knowledge and care delivery. To address this, the Pediatric Hematology Oncology Chapter of the Indian Academy of Pediatrics (IAP-PHO) is issuing evidence-based regional guidelines tailored to the Indian context. The primary objective of these guidelines is to establish nationally accepted standards for the diagnosis, comprehensive management, and prevention of thalassemia syndromes, incorporating the latest and locally relevant evidence. These evidence-based guidelines were developed through structured deliberations by 67 national experts under the IAP-PHO, incorporating iterative literature review, expert consensus, and context-specific considerations for India. The evidence quality (levels A-D, X) and strength of recommendation (strong, moderate, weak) are graded using the updated American Academy of Pediatrics framework. These guidelines provide a comprehensive, evidence-based framework for thalassemia care in India, encompassing prevention, diagnosis, transfusion and chelation, complication management, curative therapies and systems-based care, including day-care services and transition to adult care. Regular transfusion therapy with leukodepleted packed red cells to maintain pre-transfusion hemoglobin of 9.5–10.5 g/dL is the cornerstone of management in transfusion-dependent thalassemia (TDT), with individualized adjustment in special situations such as cardiac dysfunction. Iron chelation therapy should be initiated after 10–20 transfusions or when serum ferritin (SF) exceeds 1000 ng/mL; oral deferasirox is the preferred first-line agent. Combination therapy using deferasirox, and/or deferiprone and/or desferrioxamine is recommended when monotherapy with either deferasirox or deferiprone fails to reduce SF to < 2500 ng/mL or in the case of poor tolerance to one agent or when there is evidence of significant organ iron overload on T2*MRI (magnetic resonance imaging); de-escalation of chelation is recommended when SF approaches < 500 ng/mL. Comprehensive multidisciplinary care, incorporating systematic screening and timely interventions for cardiac, hepatic, endocrine, and skeletal complications, is strongly recommended. Early counseling for hematopoietic stem cell transplantation (HSCT) should be offered at diagnosis, with transplantation preferably performed at a younger age. Universal antenatal screening, cascade screening, and access to prenatal diagnosis, are critical to reducing disease burden. Emerging disease-modifying therapies may be considered in selected patients, with evolving pediatric data. Delivery of care through dedicated thalassemia day-care centers and structured transition to adult services is recommended to ensure continuity of care and best quality of life.

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder characterized by the absence of radius in the forearms and a decrease in platelet count. The molecular basis of TAR syndrome is linked to a heterozygous minimal deletion within the 1q21.1 region spanning 200 k bases (kb), resulting in a null allele and a nucleotide variation in RBM8A resulting in a hypomorphic allele. Previous studies have identified pathogenic variants in the coding regions of the RBM8A gene as the cause of TAR syndrome. However, the involvement of non-coding variants in disease pathogenesis remains largely unexplored. We investigated the association of a non-coding 3' UTR variant, c.*6C>T, in RBM8A with TAR syndrome in three individuals from two unrelated families of Indian origin. Our study provides evidence that this variant is associated with decreased stability of the transcript and is a hypomorphic allele with disease-causing impact when in trans with a null allele (1q21.1 deletion). The present work is the first application of an mRNA stability assay to directly detect RNA degradation in patients with non-coding RBM8A variants causing TAR syndrome.

To determine the impact of enzyme replacement therapy (ERT) in patients with late onset Pompe disease (LOPD) in terms of change in motor and respiratory status, along with challenges in obtaining multi-disciplinary care to manage the multi-systemic aspects of disease. This was a retrospective chart review of patient data, collected from seven tertiary care centres across India. All patients of late onset Pompe disease that have received enzyme replacement therapy were included and a descriptive analysis of data was performed. Twenty two patients of LOPD were initiated on ERT and included in this data analysis, with demise of three patients and incomplete follow-up of five patients. Motor function assessment, in terms of 6 min walk test (6MW) and change in ambulatory status, showed improvement/stabilization of distance walked in 6 min for three of four patients, although one of three lost ambulation thereafter due to severe COVID infection. One patient showed gradual deterioration in 6 MW distance with 6.7

Spinal muscular atrophy (SMA) research has focused predominantly on paediatric populations, with limited adult data from low- and middle-income countries (LMICs). We prospectively recruited suspected SMA patients (age ≥ 12 years) into a neuromuscular disease cohort at a tertiary centre in northern India, using phenotyping, creatine kinase, electrophysiology and genetic testing. Forty genetically confirmed patients were included (median age 20.5 years; mean symptom duration 14.7 ± 10.9 years). Proximal lower-limb weakness was the commonest presentation (82.5%). Forty-five percent were misdiagnosed as muscular dystrophy or congenital myopathy. Three SMA patients received risdiplam. Our cohort highlights the diagnostic challenges of adult SMA and supports a genetics-first approach. Early genetic confirmation shortens diagnostic delay, reduces misclassification and helps eligible patients benefit as disease-modifying therapies become more affordable in resource-limited settings.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, with a wide range of clinical manifestations. It is caused by pathogenic variants in the CYP21A2 gene causing deficiency of steroid 21-hydroxylase enzyme. Knowledge of the variant spectrum, which varies significantly across populations and ethnic groups, is essential for developing effective screening strategies to improve the diagnosis of 21-hydroxylase deficiency, provide accurate prognosis and reproductive options. CYP21A2 gene was amplified by highly specific primer pairs. Sequencing, multiplex ligation dependent probe amplification (MLPA) and fragment analysis were employed to determine pathogenic variants (including point variants and large deletion duplications) in 315 unrelated Asian Indian patients with CAH. Variants were detected in 94.3

Background: Our understanding of the genetic architecture of moyamoya disease (MMD) and idiopathic intracranial major artery stenosis/occlusion (ICASO) has been predominantly based on the East Asian population. There is scarce data on MMD/ICASO genetics in the South Asian population. We aimed to explore the genetics of MMD and ICASO in the Indian population by identifying population-specific variations that are unique to the Indian population, previously unknown dual pathogenic hits, and probably new genes which were never before linked to these disorders in our first unified large-scale genetic profile in India. Methods: We enrolled patients who met the criteria for both MMD and ICASO from our stroke registry. Whole exome sequencing (WES) was performed on all participants; a few cases additionally had whole genome sequencing (WGS) for a more comprehensive genetic map. Identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria, and virtual diagnostic panels were applied to the exome data. Sanger confirmation, family-based (trio) testing, gene burden testing, and a population-wide GWAS are planned as part of this ongoing study. Results: To date, we recruited 71 MMD, 57 ICASO, 62 with early-onset stroke, which also includes arterial dissection, and 66 healthy controls. In typical MMD cases, RNF213 variants appeared in 20% of cases, including the well-known p.Arg4810Lys mutation and novel missense and splice-site (c.10424-2A>C) changes. Additionally, MTHFR, SMARCAL1, ABCC6 (pathogenic), KDR, PCNT, COL4A2, and novel ANO1 association were identified, all showing typical MMD clinical and imaging characteristics. In ICASO cases, RNF213 variants were present in 8.5%, with additional NOTCH3, NOS3, KRIT1, and SLC1A3. Most remarkably, we have identified novel dual-hit combinations (RNF213–TGFBR1, RNF213–SERPIND1) in ICASO cases. The genetic patterns in both MMD and ICASO were notably different from those in stroke and healthy individuals, with multiple mutations unique to Indian patients. Conclusions: Our Indian genomic study uncovers the molecular architecture of MMD and ICASO in the South Asian population, which should pave the way for larger multicentre studies in South Asia.