About

Vimla S. Aggarwal is an Associate Professor of Pathology and Cell Biology at Columbia University Irving Medical Center. Her research focuses on the identification of the molecular basis of genetically heterogeneous disorders, such as autism, and the translation of new genetic technologies into the diagnostic arena to improve patient care. She holds additional administrative roles including Assistant Director of the Laboratory of Personalized Genomic Medicine and Director of the Laboratory of Genetics and Genomics. Dr. Aggarwal's work involves utilizing high-resolution tissue slide imaging and advanced genetic analysis to better understand complex genetic conditions. Her contributions extend to clinical and translational research, emphasizing the application of genomic medicine to diagnose and manage various genetic disorders.

Research topics

• Genetics
• Biology
• Neuroscience
• Computational biology

Selected publications

• Addendum: Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)

  Genetics in Medicine · 2025-09-10

  articleOpen access
  PublisherOA PDFDOI

• RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

  Nature Communications · 2025-02-17 · 2 citations

  articleOpen access

  SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

  PublisherOA PDFDOI

• Laboratory considerations for GRCh37 to GRCh38 reference genome transition: A laboratory quality assurance bulletin of the American College of Medical Genetics and Genomics (ACMG)

  Genetics in Medicine Open · 2025-01-01

  articleOpen access1st authorCorresponding

  Since the initial publication from the Human Genome Project, successive human genome reference versions, called assemblies or builds, have been released. Each new version has benefited from technological advancements and additional data, improving both the overall quality and the representation from diverse populations. The most recent build, Genome Research Consortium (GRC) Human Build 38 (GRCh38), also known as hg38, was released in 2013, 4 years after the previous build, GRCh37 (hg19). Because of the timing of this release and that of the broad availability of next-generation sequencing, many clinical bioinformatics pipelines were developed and validated using the GRCh37 reference sequence.

  PublisherOA PDFDOI

• ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes

  Molecular Genetics and Metabolism · 2024-03-02 · 8 citations

  articleOpen access
  PublisherOA PDFDOI

• Copy Number Analysis of Whole Exome Sequencing Data

  American Journal of Clinical Pathology · 2024-10-01

  articleOpen access

  Abstract Background Genetic alterations implicated in constitutional disorders range in size from single nucleotide substitutions to losses and gains of millions of bases. Whole exome sequencing (WES) captures many clinically relevant variants, but an analytic pipeline optimized for detection of small substitutions, insertions, and deletions may miss pathogenic copy number variants (CNVs). Historically, our laboratory performed separate cytogenetic tests to evaluate for larger genomic imbalances. Addition of copy number analysis to our WES pipeline could improve the assay’s diagnostic yield. This study describes part of our strategy to validate copy number analysis of our constitutional whole exome sequencing data. Methods We identified 18 CNV specimens that underwent both chromosomal microarray analysis (CMA) and WES between 2017 and 2023. Variants included 13 deletions (size range 14Kb-2Mb) and 5 duplications (size range 325Kb-10Mb). The standard method of constitutional copy number analysis in our clinical laboratory is CMA using the Affymetrix Cytoscan HD Array and analysis software. CNVs identified on CMA were reviewed with reference to the Database of Genomic Variants and multiple academic hospital databases. WES was performed on an Illumina sequencing system following capture-based library enrichment with the Integrated DNA Technologies xGen Exome Research, CNV Backbone, Human mtDNA Research, and Human ID Research Panel probes. CNVs identified on WES were called using the Broad Institute’s Genomic Analysis Toolkit (GATK) with a quality score cutoff of 120. Whole exome sequencing data was visualized on the Integrative Genomics Viewer. Results 14 out of 18 CNVs reported on CMA were also detected on WES with a quality score at or above 120 (78%). This includes 10 out of 13 deletions (77%) and 3 out of 5 duplications (60%). For both deletions and duplications, the size ranges of detected variants at or above the cutoff score and undetected variants overlapped. One duplication reported on CMA was detected on WES with a quality score below 120. Visualization of whole exome sequencing data showed variation in probe density that may have affected CNV calling. Conclusions The majority of CNVs reported after CMA (14/18, 78%) were also detected on WES data using a GATK quality score cutoff of 120. The data does not suggest an association between CNV size and detection by WES, although interpretation is limited by the small number of cases. Data visualization may be required to identify some CNVs. Future steps to characterize the limitations of copy number analysis of WES data include assessments of variance in probe density and read depth across the exome. Copy number analysis of WES data from cases with normal CMA results will also be performed for assay validation.

  PublisherOA PDFDOI

• P641: Application of AlphaMissense prediction to pathogenicity classification of missense variants from clinical exome sequencing

  Genetics in Medicine Open · 2024-01-01 · 4 citations

  articleOpen access

  Missense variants represent a significant fraction of variants of uncertain significance (VUS) from genetic testing, and their interpretation is a major challenge in clinical genetics. Google DeepMind recently developed AlphaMisense (AM), a new deep-learning model for the pathogenicity prediction of missense variants. This model is trained on their protein structure prediction tool AlphaFold2 and provides a publicly available database of predictions for all possible human missense variants. Although this model's performance has been evaluated previously, its application to a clinical setting has yet to be validated.

  PublisherOA PDFDOI

• P008: ClinGen Glucose-6-phosphate dehydrogenase (G6PD) Variant Curation Expert Panel: Addressing the need for genetic variant classification in G6PD deficiency*

  Genetics in Medicine Open · 2024-01-01 · 1 citations

  articleOpen access

  Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic condition affecting an estimated 400-500 million people worldwide and is one of the genetic causes of chronic hemolytic anemia and drug-, food-, or infection-induced hemolytic anemia. Most G6PD-deficient individuals are asymptomatic unless exposed to a triggering event (eg, fava beans, certain drugs), which can result in life-threatening acute hemolytic anemia. In neonates, G6PD deficiency increases the risk for severe hyperbilirubinemia and kernicterus, which is associated with increased morbidity and mortality.

  PublisherOA PDFDOI

• P702: Mosaic monosomy/partial trisomy 13 resulting from an unstable ring chromosome in a child with multiple congenital anomalies and developmental delay

  Genetics in Medicine Open · 2024-01-01

  articleOpen accessSenior author

  Ring chromosomes generally arise from breakage and rejoining of both chromosome arms. Ring chromosome 13 (RC 13) is a rare genetic condition with clinical features overlapping those observed in patients with linear 13q deletions. There is a phenotypic spectrum that includes: facial dysmorphism, developmental delays, and severe malformations involving the central nervous system, eyes, and other organs. The degree of mosaicism and mitotic instability of the ring in each tissue type is known to be an important factor affecting the severity of the phenotype. We report a 7-year-old female of Dominican descent with a family history notable for a paternal aunt with Asperger’s syndrome. Intrauterine growth restriction was suspected at 4 months of pregnancy and the patient had a birth weight of 2200g following a C-section at 36w6d. At age 6, she arrived from the Dominican Republic to establish care at our institution when she was admitted due to respiratory distress secondary to viral infection. She was noted to be G-tube dependent, deaf, and non-verbal with severe global developmental delay during evaluation by clinical genetics. Her weight was <1%tile (Z=-3.94) based on CDC weight-for-age data and her dysmorphic features included microcephaly, triangular face, tall forehead, hypertelorism, downslanting palpebral fissures, epicanthal folds, bilateral ptosis, micro-ophthalmia of the left eye, low-set posteriorly rotated ears, smooth philtrum, wide nasal bridge, broad nasal base, hypoplastic nares and high columella, wide-spaced nipples and hypoplastic thumbs. Axial hypotonia and distal hypertonia were also noted. Care with multiple specialties was subsequently established. Brain imaging revealed complete agenesis of the corpus callosum with associated colpocephaly of the lateral ventricles, dilatation of ventricles (posterolateral, third, and fourth), partial agenesis of the vermis of the cerebellum with mild hypoplasia of the medial and inferior cerebellar hemispheres, and inferior posterior fossa cyst. Chromosome and FISH analysis of a peripheral blood sample revealed an abnormal mosaic karyotype, with the majority of cells (90%) displaying a RC 13 [46,XX,r(13)(p11.2q34)], replacing a normal chromosome 13 homologue. The ring chromosome appeared to be unstable, as evidenced by the observation of a single cell where the RC 13 evolved into a dicentric ring 13. In another cell, the ring chromosome duplicated into a second independent ring. In 6% of cells, the ring chromosome was lost, effectively yielding monosomy 13. The in vivo distribution of the monosomy 13, deleted 13 (single RC 13), and partial trisomy 13 (dicentric RC 13 or double RC 13) cells lines was estimated to be 10%, 88%, and 2% respectively based on FISH analysis on uncultured cells. The deleted region in the major cell line containing the single RC 13 was characterized using SNP oligonucleotide microarray analysis which identified a terminal 13q32.1-q34 deletion (18.582 Mb) as well as a mosaic interstitial 13q32.1 deletion (1.472 Mb) corresponding to genomic coordinates 96,525,348-115,107,733 and 94,998588-96,470,243 respectively (hg19). The mosaic deletion points to the instability of the ring which has further lost genomic material in a percentage of cells. The total size of imbalance is 20.054 Mb and the entire deleted region includes 84 protein-coding genes, 71 of which are OMIM-annotated and 27 of which are associated with disease. In summary, we describe a patient with an extremely rare mosaic chromosomal complement with the major cell line represented by an unstable RC 13 and a minor cell line with monosomy 13. The clinical presentation included dysmorphism, multiple congenital anomalies and global developmental delay. The complexity and precise chromosomal nature of this case would not have been evident by standard chromosomal microarray analysis or next generation sequencing, underscoring the limitations of newer technologies and highlighting the importance and effectiveness of standard cytogenetic techniques for detecting mosaic findings.

  PublisherOA PDFDOI

• RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

  medRxiv · 2024-01-09 · 1 citations

  preprintOpen access

  SUMMARY SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

  PublisherOA PDFDOI

• P002: Investigating the impact of the 2022 ClinGen missense variant interpretation recommendations for cerebral creatine deficiency syndromes*

  Genetics in Medicine Open · 2024-01-01

  articleOpen access

  Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic disorders of creatine synthesis and transport due to pathogenic GAMT, GATM, or SLC6A8 variants, and frequently result in serious neurological impairment. The ClinGen CCDS Variant Curation Expert Panel (VCEP) adapted the 2015 ACMG/AMP guidelines to create a systematic framework for CCDS variant classification, thereby supporting early diagnosis, targeted therapy, and improved long-term outcomes. Missense variants are the most common variant type, but interpreting their clinical significance is challenging.

  PublisherOA PDFDOI

Frequent coauthors

• Karl S. Lang

  University of Duisburg-Essen

  348 shared

• Mike Recher

  University Hospital of Basel

  339 shared

• Armin Zittermann

  Heart and Diabetes Center North Rhine-Westphalia

  230 shared

• Angelo Azzi

  Tufts University

  228 shared

• Hans K. Biesalski

  University of Hohenheim

  226 shared

• Naidu K. Akhilender

  Central Food Technological Research Institute

  226 shared

• Arie Markel

  226 shared

• Yesim Negis

  Bahçeşehir University

  226 shared

Education

• Other

  Unknown

Awards & honors

• Scholanski Research Innovation Award in Pathology