Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Stray-Pedersen, Asbjørg; Sorte, Hanne Sørmo; Samarakoon, Pubudu; Gambin, Tomasz; Chinn, Iván K.; Akdemir, Zeynep H. Coban; Erichsen, Hans Christian; Forbes, Lisa R.; Gu, Shen; Yuan, Bo; Jhangiani, Shalini N.; Muzny, Donna M.; Rødningen, Olaug K.; Sheng, Ying; Nicholas, Sarah K.; Noroski, Lenora M.; Seeborg, Filiz O.; Davis, Carla M.; Canter, Debra; Mace, Emily M.; Vece, Timothy J.; Allen, Carl E.; Abhyankar, Harshal; Boone, Philip M.; Beck, Christine R.; Wiszniewski, Wojciech; Fevang, Børre; Aukrust, Pål; Tjønnfjord, Geir E.; Gedde‐Dahl, Tobias; Hjorth‐Hansen, Henrik; Dybedal, Ingunn; Nordøy, Ingvild; Jørgensen, Silje Fjellgård; Abrahamsen, Tore G.; Øverland, Torstein; Bechensteen, Anne Grete; Skogen, Vegard; Osnes, Liv; Kulseth, Mari Ann; Prescott, Trine; Rustad, Cecilie F.; Heimdal, Ketil; Belmont, John W.; Rider, Nicholas L.; Chinen, Javier; Cao, Tram N.; Smith, Eric A.; Caldirola, María Soledad; Bezrodnik, Liliana; Reyes, Saúl; Espinosa-Rosales, Francisco; Guerrero-Cursaru, Nina Denisse; Pedroza, Luis Alberto; Poli, Cecilia; Franco, José Luis; Vargas, Claudia Milena Trujillo; Becerra, Juan Carlos Aldave; Wright, Nicola; Issekutz, Thomas B.; Issekutz, Andrew C.; Abbott, Jordan K.; Caldwell, John S.; Bayer, Diana K.; Chan, Alice; Aiuti, Alessandro; Cancrini, Caterina; Holmberg, Eva; West, Christina; Burstedt, Magnus; Karaca, Ender; Yeşil, Gözde; Artaç, Hasibe; Bayram, Yavuz; Atik, Mehmed M.; Eldomery, Mohammad K.; Ehlayel, Mohammad; Jolles, Stephen; Flatø, Berit; Bertuch, Alison A.; Hanson, I. Celine; Zhang, Victor W.; Wong, Lee Jun; Hu, Jianhong; Walkiewicz, Magdalena; Yang, Yaping; Eng, Christine M.; Boerwinkle, Eric; Gibbs, Richard A.; Shearer, William T.; Lyle, Robert; Orange, Jordan S.; Lupski, James R.

doi:10.1016/j.jaci.2016.05.042

Cited by 229 publications

(219 citation statements)

References 87 publications

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“…PMPCA and KCND3 ; POLR1C and SCN1B ), consistent with previous reports of diagnoses in 5–7% of molecularly diagnosed cases [3, 5, 8, 9, 56, 80, 81]. These cases underscore the need for a systematic and comprehensive approach to exome variant analysis for all possible modes of inheritance as well as an updated literature review [12].…”

Section: Discussionsupporting

confidence: 87%

Lessons learned from additional research analyses of unsolved clinical exome cases

et al. 2017

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BackgroundGiven the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.MethodsWe designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.ResultsAnalysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). ConclusionAn efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0412-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Lessons learned from additional research analyses of unsolved clinical exome cases

et al. 2017

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“…24,25 In this and other studies, selection bias may have contributed to an underestimation of CNV contribution to disease, because arrays are often clinically indicated and ordered before whole-exome sequencing is considered; thus, the diagnostic evaluation may end with discovery of a pathogenic CNV, which precludes the identification of a second mendelian disorder.…”

Section: Discussionmentioning

confidence: 83%

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Posey¹,

Harel²,

et al. 2017

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BACKGROUND Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. METHODS We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. RESULTS A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P = 1.77×10−7). CONCLUSIONS In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.)

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“…The research protocol was approved by the relevant institutional review boards. Whole-exome sequencing was performed as part of an ongoing collaboration with the Baylor Hopkins Center for Mendelian Genomics (BHCMG) (Stray-Pedersen et al,2017). Exome capture was performed with the in-house-developed Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC) Core design (52 Mb, Roche NimbleGen) as described previously(Yang et al,2013).…”

Section: Methodsmentioning

confidence: 99%

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial orself-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of auto- inflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease.

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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Cited by 229 publications

References 87 publications

Lessons learned from additional research analyses of unsolved clinical exome cases

Lessons learned from additional research analyses of unsolved clinical exome cases

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

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