Scientific Publications

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31 Results


Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action

Jobanputra V, Schroeder B, Rehm HL, Shen W, Spiteri E, Nakouzi G, Taylor S, Marshall CR, Meng L, Kingsmore SF, Ellsworth K, Ashley E, Taft RJ; Medical Genome Initiative.

NPJ Genom Med. 2024 Mar 27;9(1):23. doi: 10.1038/s41525-024-00410-2. NO ABSTRACT PMID:38538605 | DOI:10.1038/s41525-024-00410-2

March 27, 2024
Rare Disease

Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders

Wigby KM, Brockman D, Costain G, Hale C, Taylor SL, Belmont J, Bick D, Dimmock D, Fernbach S, Greally J, Jobanputra V, Kulkarni S, Spiteri E, Taft RJ.

NPJ Genom Med. 2024 Feb 26;9(1):15. doi: 10.1038/s41525-024-00396-x. ABSTRACT Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations. PMID:38409289 | DOI:10.1038/s41525-024-00396-x

February 26, 2024
Rare DiseaseRPM for NICU and PICU

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

Kobren SN, Moldovan MA, Reimers R, Traviglia D, Li X, Barnum D, Veit A, Willett J, Berselli M, Ronchetti W, Sherwood R, Krier J, Kohane IS; Undiagnosed Diseases Network; Sunyaev SR.

bioRxiv [Preprint]. 2024 Feb 16:2024.02.13.580158. doi: 10.1101/2024.02.13.580158. ABSTRACT Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform “N-of-1” analyses on individual patients. The increasing sizes of ultra-rare, “N-of-1” disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We apply existing and introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We make our gene-level findings and variant-level information across the cohort available in a public-facing browser ( These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts. PMID:38405764 | PMC:PMC10888768 | DOI:10.1101/2024.02.13.580158

February 16, 2024
Rare Disease


ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Hirschenberger M, Lepelley A, Rupp U, Klute S, Hunszinger V, Koepke L, Merold V, Didry-Barca B, Wondany F, Bergner T, Moreau T, Rodero MP, Rösler R, Wiese S, Volpi S, Gattorno M, Papa R, Lynch SA, Haug MG, Houge G, Wigby KM, Sprague J, Lenberg J, Read C, Walther P, Michaelis J, Kirchhoff F, de Oliveira Mann CC, Crow YJ, Sparrer KMJ.

Nat Commun. 2023 Nov 1;14(1):6770. doi: 10.1038/s41467-023-42150-4. ABSTRACT Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling. PMID:37914730 | DOI:10.1038/s41467-023-42150-4

November 1, 2023
Rare Disease

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

Wojcik MH, Lemire G, Zaki MS, Wissman M, Win W, White S, Weisburd B, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Okur V, Oja KT, O’Leary M, O’Heir E, Morel C, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gazda HT, Ganesh VS, Ganapathy M, Gallacher L, Fu J, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bonnemann C, Beggs AH, Baxter SM, Agrawal PB, Talkowski M, Austin-Tse C, Rehm HL, O’Donnell-Luria A.

medRxiv. 2023 Aug 13:2023.08.08.23293829. doi: 10.1101/2023.08.08.23293829. Preprint. ABSTRACT BACKGROUND: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort. METHODS: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants. RESULTS: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19). CONCLUSION: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative. PMID:38328047 | PMC:PMC10849673 | DOI:10.1101/2023.08.08.23293829

August 13, 2023
Rare Disease

Isolated Absent Aortic Valves: A Unique Fetal Case With Echocardiographic, Pathologic, and Genetic Correlation

Schuchardt EL, Grossfeld P, Kingsmore S, Ding Y, Vargas LA, Dyar DA, Mendoza A, Dummer KB.

JACC Case Rep. 2023 Feb 22;11:101790. doi: 10.1016/j.jaccas.2023.101790. eCollection 2023 Apr 5. ABSTRACT We present a 22-week fetus with isolated absent aortic valve and inverse circular shunt. The pregnancy was interrupted. Here, echocardiography and pathology images demonstrate this rare entity. Whole genome sequencing revealed a potentially disease-causing variant in the APC gene. Whole genome sequencing should be considered in severe and rare fetal diseases. (Level of Difficulty: Advanced.). PMID:37077433 DOI:10.1016/j.jaccas.2023.101790

April 5, 2023
Rare Disease

The Genomic landscape of short tandem repeats across multiple ancestries

Vijayaraghavan P, Batalov S, Ding Y, Sanford E, Kingsmore SF, Dimmock D, Hobbs C, Bainbridge M. 

PLoS One. 2023 Jan 26;18(1):e0279430. doi: 10.1371/journal.pone.0279430. eCollection 2023. ABSTRACT Short Tandem Repeats (STRs) have been found to play a role in a myriad of complex traits and genetic diseases. We examined the variability in the lengths of over 850,000 STR loci in 996 children with suspected genetic disorders and 1,178 parents across six separate ancestral groups: Africans, Europeans, East Asians, Admixed Americans, Non-admixed Americans, and Pacific Islanders. For each STR locus we compared allele length between and within each ancestry group. In relation to Europeans, admixed Americans had the most similar STR lengths with only 623 positions either significantly expanded or contracted, while the divergence was highest in Africans, with 4,933 chromosomal positions contracted or expanded. We also examined probands to identify STR expansions at known pathogenic loci. The genes TCF4, AR, and DMPK showed significant expansions with lengths 250% greater than their various average allele lengths in 49, 162, and 11 individuals respectively. All 49 individuals containing an expansion in TCF4 and six individuals containing an expansion in DMPK presented with allele lengths longer than the known pathogenic length for these genes. Next, we identified individuals with significant expansions in highly conserved loci across all ancestries. Eighty loci in conserved regions met criteria for divergence. Two of these individuals were found to have exonic STR expansions: one in ZBTB4 and the other in SLC9A7, which is associated with X-linked mental retardation. Finally, we used parent-child trios to detect and analyze de novo mutations. In total, we observed 3,219 de novo expansions, where proband allele lengths are greater than twice the longest parental allele length. This work helps lay the foundation for understanding STR lengths genome-wide across ancestries and may help identify new disease genes and novel mechanisms of pathogenicity in known disease genes. PMID:36701310 DOI:10.1371/journal.pone.0279430

January 26, 2023
Gene DiscoveryRare Disease

Are we prepared to deliver gene-targeted therapies for rare diseases?

Yu TW, Kingsmore SF, Green RC, MacKenzie T, Wasserstein M, Caggana M, Gold NB, Kennedy A, Kishnani PS, Might M, Brooks PJ, Morris JA, Parisi MA, Urv TK.

Am J Med Genet C Semin Med Genet. 2023 Jan 24. doi: 10.1002/ajmg.c.32029. Online ahead of print. ABSTRACT The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments. PMID:36691939 DOI:10.1002/ajmg.c.32029

January 24, 2023
Rare Disease

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing

Wigby K, Hammer M, Tokita M, Patel P, Jones MC, Larson A, Bartolomei FV, Dykzeul N, Slavotinek A, Yip T, Bandres-Ciga S, Simpson BN, Suhrie K, Shankar S, Veith R, Bragg J, Powell C, Kingsmore SF, Dimmock D, Maron J, Davis J, Del Campo M.

Am J Med Genet A. 2023 Jan 18. doi: 10.1002/ajmg.a.63097. Online ahead of print. ABSTRACT Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder. PMID:36651673 DOI:10.1002/ajmg.a.63097

January 18, 2023
Rare DiseaseRPM for NICU and PICU


An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Mallory J. Owen, Sebastien Lefebvre, Christian Hansen, Chris M. Kunard, David P. Dimmock, Laurie D. Smith, Gunter Scharer, Rebecca Mardach, Mary J. Willis, Annette Feigenbaum, Anna-Kaisa Niemi, Yan Ding, Luca Van Der Kraan, Katarzyna Ellsworth, Lucia Guidugli, Bryan R. Lajoie, Timothy K. McPhail, Shyamal S. Mehtalia, Kevin K. Chau, Yong H. Kwon, Zhanyang Zhu, Sergey Batalov, Shimul Chowdhury, Seema Rego, James Perry, Mark Speziale, Mark Nespeca, Meredith S. Wright, Martin G. Reese, Francisco M. De La Vega, Joe Azure, Erwin Frise, Charlene Son Rigby, Sandy White, Charlotte A. Hobbs, Sheldon Gilmer, Gail Knight, Albert Oriol, Jerica Lenberg, Shareef A. Nahas, Kate Perofsky, Kyu Kim, Jeanne Carroll, Nicole G. Coufal, Erica Sanford, Kristen Wigby, Jacqueline Weir, Vicki S. Thomson, Louise Fraser, Seka S. Lazare, Yoon H. Shin, Haiying Grunenwald, Richard Lee, David Jones, Duke Tran, Andrew Gross, Patrick Daigle, Anne Case, Marisa Lue, James A. Richardson, John Reynders, Thomas Defay, Kevin P. Hall, Narayanan Veeraraghavan & Stephen F. Kingsmore

Nat Commun. 2022 Jul 26;13(1):4057. doi: 10.1038/s41467-022-31446-6. While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports ( This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases. PMID:35882841 | DOI:10.1038/s41467-022-31446-6

July 26, 2022
Newborn ScreeningRare DiseaseRPM for NICU and PICUrWGS

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