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The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins. In this study, we summarized 1,046 LGMD patients for which a precise diagnosis was identified using targeted sequencing. The most frequent phenotypes identified in the patients are LGMDR1 (19.7%), LGMDR4 (19.0%), LGMDR2 (17.5%), and MMD1 (14.5%). Among the reported genes, each of CAPN3, SGCB, and DYSF variants was reported in more than 10% of our study cohort. The most common variant SGCB p.Thr182Pro was identified in 146 (12.5%) of the LGMD patients, and in 97.9% of these patients, the variant was found to be homozygous. To understand the genetic structure of the patients carrying SGCB p.Thr182Pro, we genotyped 68 LGMD patients using a whole genome microarray. Analysis of the array data identified a large ~1 Mb region of homozygosity (ROH) (chr4:51817441-528499552) suggestive of a shared genomic region overlapping the recurrent missense variant and shared across all 68 patients. Haplotype analysis identified 133 marker haplotypes that were present in ~85.3% of the probands as a double allele and absent in all random controls. We also identified 5 markers (rs1910739, rs6852236, rs13122418, rs13353646, and rs6554360) which were present in a significantly higher proportion in the patients compared to random control set ( n = 128 ) and the population database. Of note, admixture analysis was suggestive of greater proportion of West Eurasian/European ancestry as compared to random controls. Haplotype analysis and frequency in the population database indicate a probable event of founder effect. Further systematic study is needed to identify the communities and regions where the SGCB p.Thr182Pro variant is observed in higher proportions. After identifying these communities and//or region, a screening program is needed to identify carriers and provide them counselling.

Funding Acknowledgements Type of funding sources: None. Background Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy and outcomes ranging from normal life expectancy to heart failure and sudden cardiac death, has a global prevalence of about 1 in 500. Genetic testing helps to improve care of patients with HCM and their family members as children of carriers have a 50% chance of inheriting the disease. However, there is limited availability, awareness and application of genetic testing modalities, particularly whole exome sequencing (WES), in the management of HCM in India. Purpose This study aimed to analyze the results of WES in a clinical HCM cohort in India. Methods Patients with unexplained moderate to severe cardiomyopathy presenting to our centre from 2017 to 2022 and consenting for genetic testing were included in the study. Following a thorough clinical diagnostic process including 3-generational family history, electrocardiogram and echocardiogram in all patients and exercise stress test, Holter monitoring and cardiac magnetic resonance imaging where applicable, pre-test counseling was provided and WES performed using genomic DNA isolated from whole blood samples. A total of 33 affected individuals including 1 affected family member from 32 families were processed for genetic testing. A multidisciplinary team comprising of cardiologist, cardiothoracic surgeon, physician with expertise in cardiogenetics, geneticist and genetic counselor carried out the study in a tertiary cardiac centre. Results Age of the probands (n=32) at the time of the study was 47.8±15.9 years and 24 (75%) were males. There was concomitant hypertension in 11 (34%), type 2 diabetes mellitus in 6 (19%), arrhythmias in 6 (19%) and coronary artery disease in 2 (6%) probands. Obstructive HCM was present in 2 (6%) probands. Disease-causing significant variants (Pathogenic/Likely pathogenic) were detected in 8 (25%, Table), variants of uncertain significance in 17 (53%) and no significant variants were detected in 7 cases. Cascade genetic testing of significant variants among 7 family members of 4 probands showed segregation of the pathogenic variant in 4 asymptomatic carriers. Conclusions The yield of whole exome sequencing in a clinical HCM cohort in India was 25%. Of note the rare variants of uncertain significance in the cardiomyopathy genes makes genetic counseling and disease management challenging. However, large-scale studies in the context of Indian population are expected to bring clarity on the role of these variants in disease manifestation. A multidisciplinary team approach incorporating genetic testing modalities such as whole exome sequencing and cascade screening is the way forward in the comprehensive management of patients with HCM and their families.

Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology.This was a multicenter descriptive study wherein children (18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative.There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2).WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.