Vaidehi Jobanputra - Academia.edu (original) (raw)

Papers by Vaidehi Jobanputra

Fertility and Sterility, Sep 1, 2020

OBJECTIVE: CNV involves both duplications and deletions of DNA sequences, which may cause human d... more OBJECTIVE: CNV involves both duplications and deletions of DNA sequences, which may cause human diseases. Some CNVs can be identified using targeted next generation sequencing-based preimplantation genetic testing for aneuploidy (PGTseqA). When the same patterns of CNVs are observed in multiple embryos, one of the parents may carry the CNV. In this study, we requested follow-up parental testing to confirm whether the same CNVs presenting in more than one embryo are inherited. DESIGN: Retrospective observational MATERIALS AND METHODS: PGTseqA amplifies $5000 amplicons across the human genome and evaluates the copy number of the amplicons. Validations for CNVs were performed using 5-cell samples from cell lines with known CNVs, and trophectoderm (TE) biopsies from embryos with a previously diagnosed parental structural rearrangement. Microarray testing of the couples was requested when multiple embryos from their cohorts showed the same CNV. RESULTS: Among 6782 PGTseqA cycles, 51 cycles from 42 patients showed the same CNVs in more than one embryo and 43 CNVs were observed. The size of deletions or duplications involved in CNVs ranged from 3.5 kb to 8.6 Mb, and included from 2 to 17 amplicons. Microarray results were received from 36 couples, and 94% (34 out of 36) confirmed that one of parents carried the CNVs, including one couple where one parent carried two CNVs. For the ClinVar pathogenic category, 11 out of 35 CNVs were classified as benign or not reportable, and the euploid embryos carrying the CNVs were available for transfer. Five were likely benign and 15 had uncertain significance. Finally, 2 were possibly pathogenic, 1 was likely pathogenic, and 1 was pathogenic. CONCLUSIONS: The confirmation of parental CNVs further validated the diagnostic accuracy of deletions or duplications in embryo biopsies. Genetic counseling about the PGTseqA and parental CNV results will help patients to decide whether they will transfer the embryos with parentallyinherited CNVs.

PLOS ONE, Jul 4, 2013

<p>Duodenum as seen at endoscopy demonstrating nodular mucosa with scalloping of folds (Cas... more <p>Duodenum as seen at endoscopy demonstrating nodular mucosa with scalloping of folds (Case 3).</p

Molecular Case Studies

Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic c... more Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The ATP6AP1 gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in ATP6AP1 have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations. Although the most striking and common clinical feature is hepatopathy, the phenotypic and genotypic spectrum of ATP6AP1-CDG continues to expand. Here, we report identical twins who presented with acute liver failure and jaundice. Prenatal features included cystic hygroma, atrial septal defect, and ventriculomegaly. Postnatal features included pectus carinatum, connective tissue abnormalities, and hypospadias. Whole-exome sequencing (WES) revealed a novel de novo...

Proceedings of the National Academy of Sciences of the United States of America, Apr 19, 2013

Scientific Reports, Dec 13, 2019

To test the performance of a new sequencing platform, develop an updated somatic calling pipeline... more To test the performance of a new sequencing platform, develop an updated somatic calling pipeline and establish a reference for future benchmarking experiments, we performed whole-genome sequencing of 3 common cancer cell lines (COLO-829, HCC-1143 and HCC-1187) along with their matched normal cell lines to great sequencing depths (up to 278x coverage) on both Illumina HiSeqX and NovaSeq sequencing instruments. Somatic calling was generally consistent between the two platforms despite minor differences at the read level. We designed and implemented a novel pipeline for the analysis of tumor-normal samples, using multiple variant callers. We show that coupled with a high-confidence filtering strategy, the use of combination of tools improves the accuracy of somatic variant calling. We also demonstrate the utility of the dataset by creating an artificial purity ladder to evaluate the somatic pipeline and benchmark methods for estimating purity and ploidy from tumor-normal pairs. The data and results of the pipeline are made accessible to the cancer genomics community.

medRxiv (Cold Spring Harbor Laboratory), Dec 16, 2022

Background: Rapid genome sequencing (rGS) has been shown to improve the care of critically ill in... more Background: Rapid genome sequencing (rGS) has been shown to improve the care of critically ill infants. Congenital heart disease (CHD) is a leading cause of infant mortality, and is often caused by genetic disorders, yet the utility of rGS has not been prospectively studied in this population. Methods: We conducted a prospective evaluation of the use of rGS to improve the care of infants with CHD in our cardiac neonatal intensive care unit (CNICU). Results: In a cohort of 48 infants with CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in eight (62%) cases with diagnostic results. These included two cases in whom genetic diagnoses helped avert intensive, futile interventions prior to CNICU discharge, as well as three cases in whom eye disease was diagnosed and treated in early childhood. Genetic disorders were associated with small for gestational age birth weight. Conclusions: Our study provides the first prospective evaluation of rGS for infants with CHD to our knowledge. We found that rGS diagnosed genetic disorders in 27% of cases and led to changes in management in 62% of cases with diagnostic results. Our model of care was enabled by multidisciplinary coordination between neonatologists, cardiologists, surgeons, geneticists, and genetic counselors. These findings highlight the important role for rGS in CHD and demonstrate the need for expanded study of how to implement this resource to a broader population of infants with CHD. Keywords: cardiac neonatal intensive care unit (CNICU), congenital heart disease (CHD), rapid genome sequencing (rGS) All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Kidney International Reports, May 1, 2023

Molecular Genetics and Metabolism, Apr 1, 2021

Annals of Clinical and Translational Neurology

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L‐serine from astrocy... more SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L‐serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8‐year‐old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant‐negative N‐glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L‐serine.

The American Journal of Human Genetics

Orphanet Journal of Rare Diseases

Introduction The Undiagnosed Diseases Network (UDN), a clinical research study funded by the Nati... more Introduction The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience. Methods We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic ana...

Journal of Genetic Counseling

Although genomic research offering next‐generation sequencing (NGS) has increased the diagnoses o... more Although genomic research offering next‐generation sequencing (NGS) has increased the diagnoses of rare/ultra‐rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non‐participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors—genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining parti...

Genetics in Medicine Open, 2023

Pilot and Feasibility Studies

Background The COVID-19 pandemic forced healthcare institutions and many clinical research progra... more Background The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. Methods We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in t...

Circulation: Genomic and Precision Medicine

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes... more Background: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. Methods: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who receive...

npj Genomic Medicine

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical... more Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or “primed” by ATG4D and an in vitro GABARAPL1 priming assay revealed decreas...

American Journal of Medical Genetics Part A

The increased use of next‐generation sequencing has expanded our understanding of the involvement... more The increased use of next‐generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability...

PURPOSEVariants of uncertain significance (VUS) are a common result of diagnostic genetic testing... more PURPOSEVariants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.METHODSRates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.RESULTSWe found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared to MGPs (32.6%; p<0.0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; p<0.001) whereas the use of GS compared to ES had no impact (22.2% vs 22.6%; p=ns).CONCLUSIONT...