Whole-exome sequencing as a diagnostic tool for ipex syndrome

Duong Anh Linh; Nguyen Thi Kim Lien; Nguyen Van Tung; Nguyen Thi Van Anh; Nguyen Thi Phuong Mai; Ngo Manh Tien; Tran Thi My Hanh; Nguyen Huy Hoang

doi:10.15625/2615-9023/16305

Author affiliations

Authors

Duong Anh Linh Institue of Genome Research
Nguyen Thi Kim Lien Institute of Genome Research, VAST, Vietnam
Nguyen Van Tung Institute of Genome Research, VAST, Vietnam
Nguyen Thi Van Anh Allergy, Immunology and Rheumatology Department
Nguyen Thi Phuong Mai Human Genetics Department, Vietnam National Children’s Hospital, Vietnam
Ngo Manh Tien Human Genetics Department, Vietnam National Children’s Hospital, Vietnam
Tran Thi My Hanh Human Genetics Department, Vietnam National Children’s Hospital, Vietnam
Nguyen Huy Hoang Institute of Genome Research

DOI:

https://doi.org/10.15625/2615-9023/16305

Keywords:

FOXP3, IPEX syndrome, primary immunodeficiency, Vietnamese, WES.

Abstract

Immune dysregulation-Polyendocrinopathy-Enteropathy-X-linked (IPEX) syndrome is a life-threatening congenital autoimmune disorder caused by mutations in the forkhead box protein 3 (FOXP3) gene. Typical clinical manifestations of IPEX patients are early onset of intractable diarrhea, type 1 diabetes mellitus, and skin diseases. However, other autoimmune types such as severe food allergies, autoimmune cytopenias, autoimmune respiratory illness, and mesangial glomerulonephritis may complicate IPEX diagnosis. In this study, we report a Vietnamese
1-year-old boy with IPEX syndrome due to a hemizygous missense mutation, c.1190G>A (p.Arg397Gln), in exon 12 of the FOXP3 gene (NM_014009.4). The child had dermatitis, diarrhea, respiratory infections, and splenomegaly. The patient's serum routine test results were expected, except for white blood cells and neutrophils were higher than the normal, while IgA concentration was slightly below the normal range. However, he got no signal of diabetes or failure to thrive. Whole exome sequencing was applied to identify a genetic variant, and variant validation was examined using Sanger sequencing. The patient’s genetic mutation was inherited from his mother, an obligate carrier. His father had a normal genotype. This study is the first report of IPEX syndrome in a Vietnamese patient with a mutation in the FOXP3 gene detected by WES. This study provides further evidence for the role of mutations in the FOXP3 gene in patients with IPEX syndrome and demonstrates the need for genetic counselling and prenatal testing. Our results also show that WES sequencing is an effective tool in diagnosing genetic diseases.

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References

An Y. F., Xu F., Wang M., Zhang Z. Y., Zhao X. D., 2011. Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China. Scand J Immunol, 74(3): 304–309. https://doi.org/10.1111/j.1365-3083.2011.02574.x.

Barzaghi F., Amaya Hernandez L. C., Neven B., Primary Immune Deficiency Treatment C., the Inborn Errors Working Party of the European Society for B., Marrow T., 2018a. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol, 141(3): 1036–1049. https://doi.org/10.1016/j.jaci.2017.10.041

Barzaghi F., Amaya Hernandez L. C., Neven B., Ricci S., Kucuk Z. Y., Bleesing J. J., Nademi Z., Slatter M. A., Ulloa E. R., Shcherbina A., Roppelt A., Worth A., Silva J., Aiuti A., Murguia-Favela L., Speckmann C., Carneiro-Sampaio M., Fernandes J. F., Baris S., Ozen A., Karakoc-Aydiner E., Kiykim A., Schulz A., Steinmann S., Notarangelo L. D., Gambineri E., Lionetti P., Shearer W. T., Forbes L. R., Martinez C., Moshous D., Blanche S., Fisher A., Ruemmele F. M., Tissandier C., Ouachee-Chardin M., Rieux-Laucat F., Cavazzana M., Qasim W., Lucarelli B., Albert M. H., Kobayashi I., Alonso L., Diaz De Heredia C., Kanegane H., Lawitschka A., Seo J. J., Gonzalez-Vicent M., Diaz M. A., Goyal R. K., Sauer M. G., Yesilipek A., Kim M., Yilmaz-Demirdag Y., Bhatia M., Khlevner J., Richmond Padilla E. J., Martino S., Montin D., Neth O., Molinos-Quintana A., Valverde-Fernandez J., Broides A., Pinsk V., Ballauf A., Haerynck F., Bordon V., Dhooge C., Garcia-Lloret M. L., Bredius R. G., Kalwak K., Haddad E., Seidel M. G., Duckers G., Pai S. Y., Dvorak C. C., Ehl S., Locatelli F., Goldman F., Gennery A. R., Cowan M. J., Roncarolo M. G., Bacchetta R., Primary Immune Deficiency Treatment C., the Inborn Errors Working Party of the European Society for B., Marrow T., 2018b. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J. Allergy Clin. Immunol., 141(3): 1036–1049 e1035. https://doi.org/10.1016/j.jaci.2017. 10.041

Bennett C. L., Christie J., Ramsdell F., Brunkow M. E., Ferguson P. J., Whitesell L., Kelly T. E., Saulsbury F. T., Chance F., Ochs H. D., 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics, 27(1): 20–21. https://doi.org/10.1038/83713

Chatila T. A., Blaeser F., Ho N., Lederman H. M., Voulgaropoulos C., Helms C., Bowcock A. M., 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest., 106(12): 75–81. https://doi.org/10.1172/ JCI11679

Chou J., Ohsumi T. K., Geha R. S., 2012. Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies. Curr Opin Allergy Clin Immunol, 12(6): 623–628. https://doi.org/10.1097/ACI.0b013e3283588ca6

Gambineri E., Ciullini Mannurita S., Hagin D., Vignoli M., Anover-Sombke S., DeBoer S., Segundo G. R. S., Allenspach E. J., Favre C., Ochs H. D., Torgerson T. R., 2018. Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. Front Immunol, 9: 2411. https://doi.org/10.3389/fimmu.2018.02411

Ge T., Wang Y., Che Y., Xiao Y., Zhang T., 2017. Atypical Late-Onset Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome with Intractable Diarrhea: A Case Report. Front Pediatr, 5: 267. https://doi.org/10.3389/fped.2017.00267

Gischel M. E., Beck C., & Hall M., 2009. A Mystery Diagnosis: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Recessive. Laboratory Medicine, 40(5): 303–306.. A Mystery Diagnosis: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Recessive. Laboratory Medicine, 40(5): 303–306. https://doi.org/ 10.1309/lmcxcu6gze7g8zei

Jamee M., Zaki-Dizaji M., Lo B., Abolhassani H., Aghamahdi F., Mosavian M., Nademi Z., Mohammadi H., Jadidi-Niaragh F., Rojas M., Anaya J. M., Azizi G., 2020. Clinical, Immunological, and Genetic Features in Patients with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-like Syndrome. J. Allergy Clin. Immunol Pract., 8(8): 2747–2760. https://doi.org/10.1016/j.jaip.2020.04.070

Kaur G., Goodall J. C., Jarvis L. B., Hill Gaston J. S., 2010. Characterisation of Foxp3 splice variants in human CD4+ and CD8+ T cells--identification of Foxp3Delta7 in human regulatory T cells. Mol Immunol, 48(1–3): 321–332. https://doi.org/10.1016/j.molimm. 2010.07.008

Li Z., Li D., Tsun A., Li B., 2015. FOXP3+ regulatory T cells and their functional regulation. Cell Mol. Immunol., 12(5): 558–565. https://doi.org/10.1038/cmi. 2015.10

Maffucci P., Filion C. A., Boisson B., Itan Y., Shang L., Casanova J. L., Cunningham-Rundles C., 2016. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol., 7: 220. https://doi.org/10.3389/fimmu.2016.00220

Mailer R. K., Falk K., Rotzschke O., 2009. Absence of leucine zipper in the natural FOXP3Delta2Delta7 isoform does not affect dimerization but abrogates suppressive capacity. PLoS One, 4(7): e6104. https://doi.org/10.1371/journal. pone.0006104

Martin-Santiago A., Hervas J. A., Hervas D., Rosell A., Caimari M., de Carlos J. C., Matamoros N., 2013. Diagnostic value of the skin lesions in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr. Dermatol., 30(6): e221–e222. https://doi.org/ 10.1111/pde.12126

Passerini L., Santoni de Sio F. R., Roncarolo M. G., Bacchetta R., 2014. Forkhead box

P3: the peacekeeper of the immune system. Int. Rev. Immunol., 33(2): 129–145. https://doi.org/10.3109/08830185. 2013.863303

Patey-Mariaud de Serre N., Canioni D., Ganousse S., Rieux-Laucat F., Goulet O., Ruemmele F., Brousse N., 2009. Digestive histopathological presentation of IPEX syndrome. Mod Pathol, 22(1): 95-102. https://doi.org/10.1038/ modpathol.2008.161

Powell B. R., Buist N. R. M., Stenzel P., 1982. An X-linked syndrome of diarrhea, polyendocrinopat.pdf. The journal of Pediatrics, 100(5): 731–737. https://doi.org/10.1016/s0022-3476(82)80 573-8

Seidel M.G., Boztug K., Haas O.A., 2016. Immune Dysregulation Syndromes (IPEX, CD27 Deficiency, and Others): Always Doomed from the Start? J Clin Immunol, 36(1): 6-7. https://doi.org/10.1007/ s10875-015-0218-5.

Stoddard J.L., Niemela J.E., Fleisher T.A., Rosenzweig S.D., 2014. Targeted NGS: A Cost-Effective Approach to Molecular Diagnosis of PIDs. Front Immunol, 5: 531. https://doi.org/10.3389/fimmu. 2014.00531.

Sun J., Yang L., Lu Y., Wang H., Peng X., Dong X., Cheng G., Cao Y., Wu B., Wang X., Zhou W., 2020. Screening for primary immunodeficiency diseases by next-generation sequencing in early life. Clin. Transl. Immunology, 9(5): e1138. https://doi.org/10.1002/cti2.1138

Ziegler S. F., 2006. FOXP3: of mice and men. Annu Rev Immunol, 24(1): 209–226. https://doi.org/10.1146/annurev.immunol.24.021605.090547