Publications

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.

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.

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.

Date: June 1, 2019

Cervical cancer is a growing and serious problem world-wide in women, but more acute in developing countries especially in Indian subcontinent. The main causative agent for the disease is Human Papilloma Virus (HPV). The history of the cervical cancer goes back to eighteenth century as the HPV infection is reported since 1800s. Presently, the genetic structure of HPV is well defined. Several screening tests including cytology and visual based screening and high risk HPV testing are available. Also available are various clinical and commercial diagnostic tests. However due to the lack of awareness and population-based screening programs, the morbidity and mortality rate is alarmingly high. There are new emerging biomarkers including E6/E7 mRNA, p16ink4a, markers of aberrant S-phase induction, chromosomal abnormalities and miRNAs along with advanced genotyping methods. These markers have clinical significance and are helpful in disease prevention and management. Further, recent advancement in the field of metagenomics has increased the prospects of identifying newer microbes, viruses hitherto reported thus far in the context of HPV infection. Analysis of HPV cases using modern tools including genotyping using more powerful biomarkers is envisaged to enhance the prospects of early diagnosis, better prognosis, more reliable treatment and eventual management of the disease.

Date: January 9, 2020

“Familial hypercholesterolemia (FH), an autosomal codominant disorder characterized by very high low-density lipoprotein cholesterol, is strongly associated with premature coronary artery disease.
Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives, and cascade screening in their relatives.”

Date: February 1, 2020

Epstein Barr Viral infection is a common childhood infection in India and is also nearly 100 % etiologically associated with pediatric Hodgkin Lymphoma (HL). The main question in EBV immunobiology has been, why only a small subset of infected individuals develop EBV associated malignancies, while the vast majority carry this virus asymptomatically for life. Natural Killer (NK) cells, with a phenotype of CD56dim CD16+ exhibit potent cytotoxicity towards both virus infected cells and transformed cells and hence have been considered to be crucial in preventing the development of symptomatic EBV infection and lymphoma. In order to get an insight into the various possible molecular aspects of NK cells, in the pathogenesis of both these EBV mediated diseases in children we studied the whole transcriptome of MACS sorted CD56dim CD16 + NK cells from four patients from each of the three groups of children viz. Infectious Mononucleosis (IM), HL and age matched controls by using a massively parallel sequencing approach. NK cells from both IM and HL had down-regulated innate immunity and chemokine signaling genes. While down-regulation of genes responsible for polarization of the secretory apparatus, activated NK cell signaling and MAP kinase signaling were exclusive to NK cells in patients with IM, in NK cells of HL, specifically, genes involved in extracellular matrix (ECM) – receptor interaction, cytokine-cytokine receptor interaction, TNF signaling, Toll-like receptor signaling pathway and cytosolic DNA-sensing pathways were significantly down-regulated. Enrichment analysis showed STAT3 to be the most significant transcription factor (TF) for the down-regulated genes in IM, whereas, GATA1 was found to be the most significant TF for the genes down-regulated in HL. Analysis of protein interaction network identified functionally important protein clusters. Top clusters, comprised of down-regulated genes, involved in signaling and ubiquitin-related processes and pathways. These may perhaps be responsible for the hypo-responsiveness of NK cells in both diseases. These possibly point to different deficiencies in NK cell activation, loss of activating receptor signaling and degranulation in IM, versus loss of cytokine and chemokine signaling in HL, in the two EBV associated pathologies investigated. Various suppressed molecules and pathways were novel, which have not been reported earlier and could therefore be potential targets for immunotherapy of NK cell reactivation in both the diseases in future.

Date: January 21, 2020

The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal defects of the pelvis and lower limbs. We report here a fetus with a novel multiple malformation syndrome associated with sacrococcygeal agenesis, bilateral lower limb aplasia, hypoplastic left heart, bilateral lung hypoplasia, hydroureteronephrosis, and nonimmune fetal hydrops, found to have a homozygous nonsense variant in the TBX4 gene. We propose that biallelic variants in the TBX4 gene are associated with a severe syndromic phenotype of sacrococcygeal agenesis and lower limb reduction defects.

Date: January 10, 2020

Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies. Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene in an Indian family with ARAS. The above‐mentioned genetic anomaly was a missense variation in exon 26 of the COL4A3 gene (chr2:228137797G>A; c.1891G>A) that resulted in the amino acid substitution of Arginine for Glycine at codon 631 (p.Gly631Arg) that was present in the heterozygous state in the asymptomatic parents and homozygous state in the male offspring who presented with early‐onset end‐stage renal disease, lenticonus and hearing loss. The patient (male offspring) underwent successful renal transplantation with his mother as a donor.

Date: December 11, 2019

Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to erlotinib by carrying out whole exome sequencing, quantitative proteomic and phosphoproteomic profiling. We observed amplification of several genes including AXL kinase and transcription factor YAP1 resulting in protein overexpression. We also observed expression of constitutively active mutant MAP2K1 (p.K57E) in erlotinib resistant SCC-R cells. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. We demonstrate that erlotinib-resistant cells are sensitive to MAPK pathway inhibition. This study revealed multiple genetic, proteomic and phosphoproteomic alterations associated with erlotinib resistant SCC-R cells. Our data indicates that therapeutic targeting of MAPK pathway is an effective strategy for treating erlotinib-resistant HNSCC tumors.

Date: December 9, 2019

Abstract
Background
Studies evaluating next‐generation sequencing (NGS) for retinal disorders may not reflect clinical practice. We report results of retrospective analysis of patients referred for clinical testing at two institutions (US and India).

Methods
This retrospective study of 131 patients who underwent clinically validated targeted NGS or exome sequencing for a wide variety of clinical phenotypes categorized results into a definitive, indeterminate, or negative molecular diagnosis.

Results
A definitive molecular diagnosis (52%) was more common in the India cohort (62% vs. 39%, p = .009), while an indeterminate molecular diagnosis occurred only in the US cohort (12%). In the US cohort, a lower diagnostic rate in Hispanic, non‐Caucasians (23%) was seen compared to Caucasians (57%). The India cohort had a high rate of homozygous variants (61%) and different frequency of genes involved compared to the US cohort.

Conclusion
Despite inherent limitations in clinical testing, the diagnostic rate across the two cohorts (52%) was similar to the 50%–65% diagnostic rate in the literature. However, the diagnostic rate was lower in the US cohort and appears partly explained by racial background. The high rate of consanguinity in the Indian population is reflected in the high rate of homozygosity for pathogenic mutations and may have implications for population level screening and genetic counseling. Clinical laboratories may note diagnostic rates that differ from the literature, due to factors such as heterogeneity in racial background or consanguinity rates in the populations being tested. This information may be useful for post‐test counseling.

Date: April 10, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in ~3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting enzyme2 (ACE2) cell surface protein to invade the host cell. The SARS-CoV-2 S-protein has acquired mutations that increase its affinity to human ACE2 by ~10-15-fold compared to SARS-CoV S-protein, making it highly infectious. In this study, we assessed if ACE2 polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein interaction. Our comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. Using recently reported structural data and a recent S-protein-interacting synthetic mutant map of ACE2, we have identified natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs. Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Overall, ACE2 variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV epidemics, however, are likely to play an important role in altering susceptibility to CoVs.

Date: February 20, 2020

Tuberculosis is the leading cause of death among infectious diseases worldwide. Detection of Mycobacterium tuberculosis (Mtb), using routine culture-based methods is time consuming resulting in delayed diagnosis and poor treatment outcomes. Currently available molecular tests provide faster diagnosis but are able to screen only limited hot-spot mutations. Whole genome sequencing from direct sputum offers a potential solution, however, due to the presence of other microbes and host DNA its use in diagnostic testing remains challenging.
In this study, we present a targeted Mtb-enrichment assay for lineage-4 coupled with an improved analysis pipeline that uses 1657 bacterial taxa as background for reducing non-Mtb genome from sputum DNA. This method drastically improved the recovery of Mtb DNA from sputum (Mtb alignment increased from 3% to >65%) as compared to non-enrichment-based sequencing. We obtained 99% Mtb genome coverage as compared to 49% in non-enriched sputum sequencing. We were able to identify Mtb positive samples from controls with 100% accuracy using Mpt64 gene coverage. Our method not only achieved 100% sensitivity to resistance variants profiled by line probe assay (LPA), but also outperformed LPA in determining drug resistance based on phenotypic drug susceptibility tests for 6 anti-tuberculosis drugs (accuracy of 97.7% and 92.8% by enriched WGS and LPA, respectively).

Date: December 27, 2019

Familial Hypercholesterolemia (FH), an autosomal co-dominant disorder characterized by very high LDL cholesterol, is strongly associated with premature coronary artery disease. Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives and cascade screening in their relatives.

Date: December 4, 2019

The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

Date: February 5, 2019

A 21year-old man presented with involuntary jerky movements of his hands and head since age 13. Initially mild, they had progressed to moderate severity over the last few years. The movements could come in ‘spells’ intermittently in the early years. His whole body could tremble when he was anxious, concentrating on an activity or riding his scooter. While he could still do all activities unhindered, and symptoms were mostly an inconvenience, they were increasingly causing embarrassment. Family history was negative. He had never used alcohol. On examination, myoclonic jerking of the neck and both hands was present at rest This article is protected by copyright. All rights reserved. and action. (Video 1, Segment 1) There was no involvement of face, trunk or lower limbs. Brain MRI, metabolic testing, EEG and SSEP were normal. A clinical diagnosis of Myoclonus-Dystonia (M-D) syndrome was made.

Date: August 14, 2018

Snigdha Majumder, Rakshit Shah, Jisha Elias, Malini Manoharan, Priyanka Shah, Anjali Kumari, Papia Chakraborty, Vasumathi Kode, Yogesh Mistry, Karunakaran Coral, Bharti Mittal, Sakthivel Murugan SM, Lakshmi Mahadevan, Ravi Gupta, Amitabha Chaudhuri & Arati Khanna-Gupta. Lynch Syndrome (LS) is an inherited heterozygous autosomal dominant disorder which predisposes affected individuals to the risk of developing colorectal cancer (CRC) as well as to endometrial carcinomas, tumours of the stomach, small intestines, ureter, brain, pelvis and prostate among others1. It is the most common hereditary CRC syndrome accounting for 2–5% of all CRCs. In the developed world, the estimated disease frequency ranges from 1:370 to 1:20002 but no prevalence details have been officially reported from developing nations to date. In India, while the overall incidence of CRC is comparatively lower than in the west, a large percentage of patients develop CRC before the age of 45 with a higher proportion (10–15%) of LS-CRC cases3.

Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1. Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function of immune homeostasis to protect itself from immune- mediated elimination [1, 2]. By expressing high levels of PD- L1, tumor cells engage PD-1 receptors on T cells, suppressing their anti-tumor activity and escaping T cell-mediated killing. By blocking PD-1 and PD-L1 signaling, the checkpoint inhibitors remove the brakes on T cells imposed by the tumor and enhance their anti-tumor activity

Date: February 21, 2018

Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1. Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function of immune homeostasis to protect itself from immune-mediated elimination [1, 2]. By expressing high levels of PD-L1, tumor cells engage PD-1 receptors on T cells, suppressing their anti-tumor activity and escaping T cell-mediated killing. By blocking PD-1 and PD-L1 signaling, the checkpoint inhibitors remove the brakes on T cells imposed by the tumor and enhance their anti-tumor activity [3].

Date: January 16, 2018

Jammu and Kashmir (J&K), the Northern most State of India, has been under-represented or altogether absent in most of the phylogenetic studies carried out in literature, despite its strategic location in the Himalayan region. Nonetheless, this region may have acted as a corridor to various migrations to and from mainland India, Eurasia or northeast Asia. The belief goes that most of the migrations post-late Pleistocene were mainly male dominated, primarily associated with population invasions, where female migration may thus have been limited. To evaluate female-centered migration patterns in the region, we sequenced 83 complete mitochondrial genomes of unrelated individuals belonging to different ethnic groups from the state. We observed a high diversity in the studied maternal lineages, identifying 19 new maternal sub-haplogroups (HGs). High maternal diversity and our phylogenetic analyses suggest that the migrations post-Pleistocene were not strictly paternal, as described in the literature. These preliminary observations highlight the need to carry out an extensive study of the endogamous populations of the region to unravel many facts and find links in the peopling of India.

Date: May 21, 2017

Muthusamy B, Selvan LDN, Nguyen TT, Manoj J, Stawiski EW, Jaiswal BS, Wang W, Raja R, Ramprasad VL, Gupta R, Murugan S, Kadandale JS, Prasad TSK, Reddy K, Peterson A, Pandey A, Seshagiri S, Girimaji SC, Gowda H, OMICS, 2017 May;21(5):295-303. Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next- generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

Date: September 16, 2016

Manitoba-oculo-tricho-anal (MOTA) syndrome is very rare syndrome characterized by aberrant hairline, eye anomalies (ocular hypertelorism, cryptophthalmos, and upper eyelid colobomas), bifid nose, omphalocele and anorectal anomalies. MOTA syndrome was first reported in 1992 in Oji-cree community from the Island Lake region of Manitoba, Canada. Till date very few cases of MOTA have been reported and none from India. We report first case of MOTA syndrome from India. A two month old male baby was brought with complaints of defect in right upper eye lid since birth. He was the second born child of a second degree consanguineously married couple at 37 weeks of gestation. On physical examination, the baby had right upper eyelid coloboma, ocular hypertelorism, bifid nose, small nasal ala and bilateral undescended testis. Investigations revealed high anorectal anomaly and right renal agenesis. Whole exome sequencing showed homozygous nonsense variation in exon 25 of the FREM1 gene that resulted in a stop codon. This case gains importance as it is the first case of MOTA being reported from India and bilateral undescended testis which was seen this case is an addition to the variable clinical spectrum of MOTA.

Date: April 25, 2016

We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption.

Date: August 31, 2012

With over 1.3 billion people, India is estimated to contain three times more genetic diversity than Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While genomes from people of European and Asian descent have been sequenced, only recently has a single male genome from the Indian subcontinent been published at sufficient depth and coverage. In this study we have sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala.

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

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