At MedGenome, we are deeply focused on continuous innovation, and publishing our findings for the larger benefit of the genetic testing community. Read through our publications for details of our latest work.
Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene
Date: March 28, 2023
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 ~1Mb 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.
Date: March 21, 2022
Autosomal aneuploidies occurring in chromosomes other than 13, 18, and 21 and sex chromosomal aneuploidies are referred to as ‘Rare autosomal aneuploidies’ (RAAs).
A prenatal incidence of 0.41% is noted for RAAs on chorionic villus sampling (CVS) procedures. Aneuploidies in autosomes other than 13, 18, and 21 and sex chromosomal aneuploidies may result in increased fetal-placental diseases
such as non-viable pregnancy, early miscarriage, intrauterine fetal growth restriction, uniparental disomy, multiple congenital anomalies, fetal demise, or normal live birth . The screen-positive rate of RAAs on NIPT is 0.04% to 0.83%.
However, the PPV of RAAs on NIPT is found to be 6–29%.
The increased false positives for RAAs on NIPT are most commonly due to confined placental mosaicism (CPM)  but may also arise due to vanishing twin or maternal malignancies.
Clinically relevant abnormalities can be detected in 30–75% of the high-risk cases of RAAs in NIPT .
Profile of Pathogenic Mutations and Evaluation of Germline Genetic Testing Criteria in Consecutive Breast Cancer Patients Treated at a North Indian Tertiary Care Center
Date: October 2, 2021
ABSTRACT Background. The burden of hereditary breast cancer in India is not well defined. Moreover, genetic testing criteria (National Comprehensive Cancer Network [NCCN] and Mainstreaming Cancer Genetics [MCG] Plus) have never been validated in the Indian population. Methods. All new female breast cancer patients from 1st March 2019 to 28th February 2020 were screened. Those providing informed consent and without previous genetic testing were recruited. Multigene panel testing (107 genes) by next-generation sequencing was performed for all patients. The frequency of pathogenic/likely pathogenic (P/ LP) mutations between patients qualifying and not qualifying the testing criteria was compared and their sensitivity was computed. Results. Overall, 275 breast cancer patients were screened and 236 patients were included (median age 45 years); 30 patients did not consent and 9 patients previously underwent genetic testing. Thirty-four (14%) women had a positive family history and 35% had triple-negative breast cancer. P/LP mutations were found in 44/236 (18.64%).
Matrilineal analysis of mutations in the DMD gene in a multigenerational South Indian cohort using DMD gene panel sequencing
Duchenne muscular dystrophy (DMD) is an X‐linked recessive neuromuscular disorder characterised by progressive irreversible muscle weakness, primarily of the skeletal and the cardiac muscles. DMD is characterised by mutations in the dystrophin gene, resulting in the absence or sparse quantities of dystrophin protein. A precise and timely molecular detection of DMD mutations encourages interventions such as carrier genetic counselling and in undertaking therapeutic measures for the DMD patients.
In this study, we developed a 2.1 Mb custom DMD gene panel that spans the entire DMD gene, including the exons and introns. The panel also includes the probes against 80 additional genes known to be mutated in other muscular dystrophies. This custom DMD gene panel was used to identify single nucleotide variants (SNVs) and large deletions with precise breakpoints in 77 samples that included 24 DMD patients and their matrilineage across four generations. We used this panel to evaluate the inheritance pattern of DMD mutations in maternal subjects representing 24 DMD patients.
Here we report our observations on the inheritance pattern of DMD gene mutations in matrilineage samples across four generations. Additionally, our data suggest that the DMD gene panel designed by us can be routinely used as a single genetic test to identify all DMD gene variants in DMD patients and the carrier mothers.
We report clinical profile of hundred and nine patients with SARS CoV-2 infection, and whole genome sequences (WGS) of seven virus isolates from the first reported cases in India, with various international travel histories. Comorbidities such as diabetes, hypertension, and cardiovascular disease were frequently associated with severity of the disease. WBC and neutrophil counts showed an increase, while lymphocyte counts decreased in patients with severe infection suggesting a possible neutrophil mediated organ damage, while immune activity may be diminished with decrease in lymphocytes leading to disease severity. Increase in SGOT, SGPT and blood urea suggests the functional deficiencies of liver, heart, and kidney in patients who succumbed to the disease when compared to the group of recovered patients. The WGS analysis showed that these isolates were classified into two clades: I/A3i, and A2a (four according to GISAID: O, L, GR, and GH). Further, WGS phylogeny and travel history together indicate possible transmission from Middle East and Europe. Three S protein variants: Wuhan reference, D614G, and Y28H were identified predicted to possess different binding affinities to host ACE2.
NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results – a pilot study
Date: November 2, 2020
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
Keywords: Carrier screening, Cystic fibrosis, Hearing loss, Pompe disease, Asian Indians
Ophthatome™: an integrated knowledgebase of ophthalmic diseases for translating vision research into the clinic
Date: November 10, 2020
Background: Medical big data analytics has revolutionized the human healthcare system by introducing processes that facilitate rationale clinical decision making, predictive or prognostic modelling of the disease progression and management, disease surveillance, overall impact on public health and research. Although, the electronic medical records (EMR) system is the digital storehouse of rich medical data of a large patient cohort collected over many years, the data lack sufficient structure to be of clinical value for applying deep learning methods and advanced analytics to improve disease management at an individual patient level or for the discipline in general. Ophthatome™ captures data contained in retrospective electronic medical records between September 2012 and January 2018 to facilitate translational vision research through a knowledgebase of ophthalmic diseases.
Methods: The electronic medical records data from Narayana Nethralaya ophthalmic hospital recorded in the MS-SQL database was mapped and programmatically transferred to MySQL. The captured data was manually curated to preserve data integrity and accuracy. The data was stored in MySQL database management system for ease of visualization, advanced search functions and other knowledgebase applications.
Results: Ophthatome™ is a comprehensive and accurate knowledgebase of ophthalmic diseases containing curated clinical, treatment and imaging data of 581,466 ophthalmic subjects from the Indian population, recorded between September 2012 and January 2018. Ophthatome™ provides filters and Boolean searches with operators and modifiers that allow selection of specific cohorts covering 524 distinct ophthalmic disease types and 1800 disease sub-types across 35 different anatomical regions of the eye. The availability of longitudinal data for about 300,000 subjects provides additional opportunity to perform clinical research on disease progression and management including drug responses and management outcomes. The knowledgebase captures ophthalmic diseases in a genetically diverse population providing opportunity to study genetic and environmental factors contributing to or influencing ophthalmic diseases.
Conclusion: Ophthatome™ will accelerate clinical, genomic, pharmacogenomic and advanced translational research in ophthalmology and vision sciences.
Date: June 1, 2020
BACKGROUND Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.
OBJECTIVES This analysis used summary statistics from a prior genome-wide association study to derive a new GPSCAD for South Asians.
METHODS This GPSCAD was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPSCAD reference distribution was built using wholegenome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPSCAD reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.
RESULTS The GPSCAD, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian casecontrol study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPSCAD distribution—ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each). CONCLUSIONS The new GPSCAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment. (J Am Coll Cardiol 2020;76:703–14) © 2020 by the American College of Cardiology Foundation.
Late-onset KMT2B-related dystonia in an Indian patient with normal cognition, dystonic opisthotonus and lack of oromandibular and laryngeal involvement
Date: April 14, 2020
KMT2B-related dystonia is characterized by childhood-onset and progressive disease course with prominent lower-limb, cervical, cranial, and laryngeal involvement [ 1 ]. Developmental delay and intellectual disability are commonly reported [ 1 , 2 ]. Here we are reporting an Indian patient with KMT2B-related dystonia who had a disease onset at the age of 19 years. Other interesting features in our patient were normal cognition, dystonic opisthotonus, and absence of oromandibular and laryngeal dystonia.
Robinow Syndrome and Brachydactyly: An Interplay of High-Throughput Sequencing and Deep Phenotyping in a Kindred
Date: March 1, 2020
We report a family with a spectrum of short stature, craniofacial dysmorphism, and digital anomalies in a father and 2 daughters, with the youngest (proband) displaying a severe phenotype. Clinically, autosomal dominant Robinow syndrome (ADRS) was diagnosed. Whole-exome sequencing identified a heterozygous pathogenic BMP2 variant in the father and his daughters. The phenotype of short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies related to BMP2 haploinsufficiency has some facial and digital resemblance to ADRS. Although this variant segregated in the affected members, it failed to explain the severe phenotype of the proband. A reanalysis of the girl’s raw data confirmed 2 disorders: a de novo likely pathogenic DVL1 variant implicated in ADRS and the familial BMP2 variant. A close interplay of high-throughput sequencing and deep phenotyping unraveled the complexities of the blended phenotype in the proband.