Swaroop Aradhya

All Publications

• Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genetics in medicine : official journal of the American College of Medical Genetics Riggs, E. R., Andersen, E. F., Cherry, A. M., Kantarci, S., Kearney, H., Patel, A., Raca, G., Ritter, D. I., South, S. T., Thorland, E. C., Pineda-Alvarez, D., Aradhya, S., Martin, C. L. 2019

  Abstract

  PURPOSE: Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.METHODS: To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen) project.RESULTS: This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidence-based classification of a variant from its potential implications for a particular individual.CONCLUSION: These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.

  View details for DOI 10.1038/s41436-019-0686-8

  View details for PubMedID 31690835

• Genetics in mainstream medicine: Finally within grasp to influence healthcare globally MOLECULAR GENETICS & GENOMIC MEDICINE Aradhya, S., Nussbaum, R. L. 2018; 6 (4): 473–80

  Abstract

  A modern genomics ecosystem has emerged. This commentary describes recent trends in clinical genomics that enable its successful integration in mainstream medicine. The rapid expansion of clinical genomics will have a positive impact on the healthcare of individuals worldwide.

  View details for PubMedID 29807392

• Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Meck, J. M., Dugan, E. K., Matyakhina, L., Aviram, A., Trunca, C., Pineda-Alvarez, D., Aradhya, S., Klein, R. T., Cherry, A. M. 2015; 213 (2)

  Abstract

  We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result.We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4).The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives.T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.

  View details for DOI 10.1016/j.ajog.2015.04.001

  View details for Web of Science ID 000358550900024

• Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. American journal of obstetrics and gynecology Meck, J. M., Kramer Dugan, E., Matyakhina, L., Aviram, A., Trunca, C., Pineda-Alvarez, D., Aradhya, S., Klein, R. T., Cherry, A. M. 2015; 213 (2): 214 e1-5

  Abstract

  We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result.We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4).The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives.T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.

  View details for DOI 10.1016/j.ajog.2015.04.001

  View details for PubMedID 25843063

• ClinGen - The Clinical Genome Resource NEW ENGLAND JOURNAL OF MEDICINE Rehm, H. L., Berg, J. S., Brooks, L. D., Bustamante, C. D., Evans, J. P., Landrum, M. J., Ledbetter, D. H., Maglott, D. R., Martin, C. L., Nussbaum, R. L., Plon, S. E., Ramos, E. M., Sherry, S. T., Watson, M. S. 2015; 372 (23): 2235-2242

  View details for DOI 10.1056/NEJMsr1406261

  View details for PubMedID 26014595

• Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay AMERICAN JOURNAL OF MEDICAL GENETICS PART A Muller, E. A., Aradhya, S., Atkin, J. F., Carmany, E. P., Elliott, A. M., Chudley, A. E., Clark, R. D., Everman, D. B., Garner, S., Hall, B. D., Herman, G. E., Kivuva, E., Ramanathan, S., Stevenson, D. A., Stockton, D. W., Hudgins, L. 2012; 158A (2): 391-399

  Abstract

  Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352  kb to 20.5  Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929  kb region for metopic craniosynostosis, a 1.08  Mb region for obstructive hydrocephalus, and a 1.84  Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.

  View details for DOI 10.1002/ajmg.a.34216

  View details for PubMedID 22190277

• Clinical and molecular delineation of the 17q21.31 microdeletion syndrome JOURNAL OF MEDICAL GENETICS Koolen, D. A., Sharp, A. J., Hurst, J. A., Firth, H. V., Knight, S. J., Goldenberg, A., Saugier-Veber, P., Pfundt, R., Vissers, L. E., Destree, A., Grisart, B., Rooms, L., Van der Aa, N., Field, M., Hackett, A., Bell, K., Nowaczyk, M. J., Mancini, G. M., Poddighe, P. J., Schwartz, C. E., Rossi, E., De Gregori, M., Antonacci-Fulton, L. L., McLellan, M. D., Garrett, J. M., Wiechert, M. A., Miner, T. L., Crosby, S., Ciccone, R., Willatt, L., Rauch, A., Zenker, M., Aradhya, S., Manning, M. A., Strom, T. M., Wagenstaller, J., Krepischi-Santos, A. C., Vianna-Morgante, A. M., Rosenberg, C., Price, S. M., Stewart, H., Shaw-Smith, C., Brunner, H. G., Wilkie, A. O., Veltman, J. A., Zuffardi, O., Eichler, E. E., de Vries, B. B. 2008; 45 (11): 710-720

  Abstract

  The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)).Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

  View details for DOI 10.1136/jmg.2008.058701

  View details for Web of Science ID 000260535600004

  View details for PubMedID 18628315

  View details for PubMedCentralID PMC3071570

• Genetic analysis of attractin homologs GENESIS Walker, W. P., Aradhya, S., Hu, C., Shen, S., Zhang, W., Azarani, A., Lu, X., Barsh, G. S., Gunn, T. M. 2007; 45 (12): 744-756

  Abstract

  Attractin (ATRN) and Attractin-like 1 (ATRNL1) are highly similar type I transmembrane proteins. Atrn null mutant mice have a pleiotropic phenotype including dark fur, juvenile-onset spongiform neurodegeneration, hypomyelination, tremor, and reduced body weight and adiposity, implicating ATRN in numerous biological processes. Bioinformatic analysis indicated that Atrn and Atrnl1 arose from a common ancestral gene early in vertebrate evolution. To investigate the genetics of the ATRN system and explore potential redundancy between Atrn and Atrnl1, we generated and characterized Atrnl1 loss- and gain-of-function mutations in mice. Atrnl1 mutant mice were grossly normal with no alterations of pigmentation, central nervous system pathology or body weight. Atrn null mutant mice carrying a beta-actin promoter-driven Atrnl1 transgene had normal, agouti-banded hairs and significantly delayed onset of spongiform neurodegeneration, indicating that over-expression of ATRNL1 compensates for loss of ATRN. Thus, the two genes are redundant from the perspective of gain-of-function but not loss-of-function mutations.

  View details for DOI 10.1002/dvg.20351

  View details for Web of Science ID 000252307200003

  View details for PubMedID 18064672

• Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs GENETICS IN MEDICINE Aradhya, S., Cherry, A. M. 2007; 9 (9): 553-559

  Abstract

  Array-based comparative genomic hybridization is ushering in a new standard for analyzing the genome, overcoming the limits of resolution associated with conventional G-banded karyotyping. The first genomic arrays were based on bacterial artificial chromosome clones mapped during the initial phases of the Human Genome Project. These arrays essentially represented multiple fluorescence in situ hybridization assays performed simultaneously. The first arrays featured a targeted design, consisting of hundreds of bacterial artificial chromosome clones limited mostly to genomic regions of known medical significance. Then came whole-genome arrays, which contained bacterial artificial chromosome clones from across the entire genome. More recently, alternative designs based on oligonucleotide probes have been developed, and all these are high-density whole-genome arrays with resolutions between 3 and 35 kb. Certain clinical circumstances are well suited for investigation by targeted arrays, and there are others in which high-resolution whole-genome arrays are necessary. Here we review the differences between the two types of arrays and the clinical contexts for which they are best suited. As array-based comparative genomic hybridization is integrated into diagnostic laboratories and different array designs are used in appropriate clinical contexts, this novel technology will invariably alter the testing paradigm in medical genetics and will lead to the discovery of novel genetic conditions caused by chromosomal anomalies.

  View details for DOI 10.1097/GIM.0b013e318149e354

  View details for Web of Science ID 000249640800001

  View details for PubMedID 17873642

• Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features AMERICAN JOURNAL OF MEDICAL GENETICS PART A Aradhya, S., Manning, M. A., Splendore, A., Cherry, A. M. 2007; 143A (13): 1431-1441

  Abstract

  Cytogenetic imbalances are the most frequently identified cause of developmental delay or mental retardation, which affect 1-3% of children and are often seen in conjunction with growth retardation, dysmorphic features, and various congenital anomalies. A substantial number of patients with developmental delay or mental retardation are predicted to have cytogenetic imbalances, but conventional methods for identifying these imbalances yield positive results in only a small fraction of these patients. We used microarray-based comparative genomic hybridization (aCGH) to study a panel of 20 patients predicted to have chromosomal aberrations based on clinical presentation of developmental delay or mental retardation, growth delay, dysmorphic features, and/or congenital anomalies. Previous G-banded karyotypes and fluorescence in situ hybridization results were normal for all of these patients. Using both oligonucleotide-based and bacterial artificial chromosome (BAC)-based arrays on the same panel of patients, we identified 10 unique deletions and duplications ranging in size from 280 kb to 8.3 Mb. The whole-genome oligonucleotide arrays identified nearly twice as many imbalances as did the lower-resolution whole-genome BAC arrays. This has implications for using aCGH in a clinical setting. Analysis of parental DNA samples indicated that most of the imbalances had occurred de novo. Moreover, seven of the 10 imbalances represented novel disorders, adding to an increasing number of conditions caused by large-scale deletions or duplications. These results underscore the strength of high-resolution genomic arrays in diagnosing cases of unknown genetic etiology and suggest that contiguous genomic alterations are the underlying pathogenic cause of a significant number of cases of developmental delay.

  View details for DOI 10.1002/ajmg.a.31773

  View details for Web of Science ID 000247760600005

  View details for PubMedID 17568414

• Novel cytogenetic alterations detected by array CGH in patients with developmental delay, dysmorphology, and mental retardation Aradhya, S., Shieh, J., Hoyme, E., Manning, M., Cherry, A. M. KARGER. 2007

  View details for Web of Science ID 000245885400029

• Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization. American journal of medical genetics. Part A Shieh, J. T., Aradhya, S., Novelli, A., Manning, M. A., Cherry, A. M., Brumblay, J., Salpietro, C. D., Bernardini, L., Dallapiccola, B., Hoyme, H. E. 2006; 140 (12): 1267-1273

  Abstract

  In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

  View details for PubMedID 16691576

• A mouse keratin 1 mutation causes dark skin and epidermolytic hyperkeratosis JOURNAL OF INVESTIGATIVE DERMATOLOGY McGowan, K. A., Aradhya, S., Fuchs, H., de Angelis, M. H., Barsh, G. S. 2006; 126 (5): 1013-1016

  Abstract

  Chemical mutagenesis in the mouse has increased the utility of phenotype-driven genetics as a means for studying different organ systems, developmental pathways, and pathologic processes. From a large-scale screen for dominant phenotypes in mice, a novel class of pigmentation mutants was identified by dark skin (Dsk). We describe a Dsk mutant, Dsk12, which models the human disease, epidermolytic hyperkeratosis (EHK). At 2 days of age, mutant animals exhibit intraepidermal blisters and erosions at sites of trauma, and by 2 weeks of age develop significant hyperkeratosis. We identified a missense mutation in mutant animals that predicts an S194P amino acid substitution in the 1A domain of Keratin 1, a known target for human mutations that cause EHK. Dsk12 recapitulates the gross pathologic, histologic, and genetic aspects of the human disorder, EHK.

  View details for DOI 10.1038/sj.jid.5700241

  View details for Web of Science ID 000238968700016

  View details for PubMedID 16528356

• Nablus mask-like facial syndrome is caused by deletion in 8q21-8q22 detected by array-based comparative genomic hybridiztion. Shieh, J. T., Aradhya, S., Manning, M. A., Cherry, A. M., Dallapiccola, B., Hoyme, H. E. B C DECKER INC. 2006: S138

  View details for Web of Science ID 000235301500352

• Dark skin mouse mutants reveal new genes involved in pigmentation 66th Annual Meeting of the Society-for-Investigative-Dermatology McGowan, K., Aradhya, S., Fuchs, H., de Angelis, M. H., Barsh, G. NATURE PUBLISHING GROUP. 2005: A151–A151

  View details for Web of Science ID 000228179901442

• The role of accessory proteins in melanocortin receptor signaling Barsh, G., Candille, S., He, L., Aradhya, S., Kerns, J. BLACKWELL MUNKSGAARD. 2004: 569

  View details for Web of Science ID 000223590800015