Медицинская библиотека · The Journal of allergy and clinical immunology · 2022

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

Similuk Morgan N, Yan Jia, Ghosh Rajarshi, Oler Andrew J, Franco Luis M, Setzer Michael R, Kamen Michael, Jodarski Colleen, DiMaggio Thomas, Davis Joie, Gore Rachel, Jamal Leila, Borges Adrienne, Gentile Nicole, Niemela Julie, Lowe Chenery, Jevtich Kathleen, Yu Yunting, Hullfish Haley, Hsu Amy P, Hong Celine, Littel Patricia, Seifert Bryce A, Milner Joshua, Johnston Jennifer J, Cheng Xi, Li Zhiwen, Veltri Daniel, Huang Ke, Kaladi Krishnaveni, Barnett Jason, Zhang Lingwen, Vlasenko Nikita, Fan Yongjie, Karlins Eric, Ganakammal Satishkumar Ranganathan, Gilmore Robert, Tran Emily, Yun Alvin, Mackey Joseph, Yazhuk Svetlana, Lack Justin, Kuram Vasudev, Cao Wenjia, Huse Susan, Frank Karen, Fahle Gary, Rosenzweig Sergio, Su Yan, Hwang SuJin, Bi Weimin, Bennett John, Myles Ian A, De Ravin Suk See, Fuss Ivan, Strober Warren, Bielekova Bibiana, Almeida de Jesus Adriana, Goldbach-Mansky Raphaela, Williamson Peter, Kumar Kelly, Dempsy Caeden, Frischmeyer-Guerrerio Pamela, Fisch Robin, Bolan Hyejeong, Metcalfe Dean D, Komarow Hirsh, Carter Melody, Druey Kirk M, Sereti Irini, Dropulic Lesia, Klion Amy D, Khoury Paneez, O' Connell Elise M, Holland-Thomas Nicole C, Brown Thomas, McDermott David H, Murphy Philip M, Bundy Vanessa, Keller Michael D, Peng Christine, Kim Helen, Norman Stephanie, Delmonte Ottavia M, Kang Elizabeth, Su Helen C, Malech Harry, Freeman Alexandra, Zerbe Christa, Uzel Gulbu, Bergerson Jenna R E, Rao V Koneti, Olivier Kenneth N, Lyons Jonathan J, Lisco Andrea, Cohen Jeffrey I, Lionakis Michail S, Biesecker Leslie G, Xirasagar Sandhya, Notarangelo Luigi D, Holland Steven M, Walkiewicz Magdalena A

СтатьяОбзорResearch Support, N.I.H., IntramuralПеревод в очереди

Аннотация

BACKGROUND

Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges.

OBJECTIVES

This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health.

METHODS

This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity.

RESULTS

Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option.

CONCLUSIONS

This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Для цитирования: Similuk Morgan N, Yan Jia, Ghosh Rajarshi, Oler Andrew J, Franco Luis M, Setzer Michael R, Kamen Michael, Jodarski Colleen, DiMaggio Thomas, Davis Joie, Gore Rachel, Jamal Leila, Borges Adrienne, Gentile Nicole, Niemela Julie, Lowe Chenery, Jevtich Kathleen, Yu Yunting, Hullfish Haley, Hsu Amy P, Hong Celine, Littel Patricia, Seifert Bryce A, Milner Joshua, Johnston Jennifer J, Cheng Xi, Li Zhiwen, Veltri Daniel, Huang Ke, Kaladi Krishnaveni, Barnett Jason, Zhang Lingwen, Vlasenko Nikita, Fan Yongjie, Karlins Eric, Ganakammal Satishkumar Ranganathan, Gilmore Robert, Tran Emily, Yun Alvin, Mackey Joseph, Yazhuk Svetlana, Lack Justin, Kuram Vasudev, Cao Wenjia, Huse Susan, Frank Karen, Fahle Gary, Rosenzweig Sergio, Su Yan, Hwang SuJin, Bi Weimin, Bennett John, Myles Ian A, De Ravin Suk See, Fuss Ivan, Strober Warren, Bielekova Bibiana, Almeida de Jesus Adriana, Goldbach-Mansky Raphaela, Williamson Peter, Kumar Kelly, Dempsy Caeden, Frischmeyer-Guerrerio Pamela, Fisch Robin, Bolan Hyejeong, Metcalfe Dean D, Komarow Hirsh, Carter Melody, Druey Kirk M, Sereti Irini, Dropulic Lesia, Klion Amy D, Khoury Paneez, O' Connell Elise M, Holland-Thomas Nicole C, Brown Thomas, McDermott David H, Murphy Philip M, Bundy Vanessa, Keller Michael D, Peng Christine, Kim Helen, Norman Stephanie, Delmonte Ottavia M, Kang Elizabeth, Su Helen C, Malech Harry, Freeman Alexandra, Zerbe Christa, Uzel Gulbu, Bergerson Jenna R E, Rao V Koneti, Olivier Kenneth N, Lyons Jonathan J, Lisco Andrea, Cohen Jeffrey I, Lionakis Michail S, Biesecker Leslie G, Xirasagar Sandhya, Notarangelo Luigi D, Holland Steven M, Walkiewicz Magdalena A. Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.. The Journal of allergy and clinical immunology. 2022. DOI: 10.1016/j.jaci.2022.06.009.

Предметные рубрики MeSH

Exome Female Genetic Testing Genomics Humans Male Phenotype Prospective Studies

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