Whole-exome Sequencing Identified a Novel Hemizygous Missense Variant in the EDA Gene in an Iranian Patient Causing Hypohidrotic Ectodermal Dysplasia

Dorgaleleh, Saeed; Oladnabi, Morteza

doi:10.22038/ijp.2022.66620.4998

Whole-exome Sequencing Identified a Novel Hemizygous Missense Variant in the EDA Gene in an Iranian Patient Causing Hypohidrotic Ectodermal Dysplasia

Document Type : original article

Authors

Saeed Dorgaleleh ¹

Morteza Oladnabi ²

¹ Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran.

² 1. Gorgan Congenital Malformations Research Center, Golestan University of Medical Sciences, Gorgan, Iran. 2. Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran.

10.22038/ijp.2022.66620.4998

Abstract

Ectodermal dysplasia (ED) is a congenital heterogenic disorder caused by the defect in the ectoderm and its derivatives. This complex disorder has different subtypes, the most common form of which is hypohidrotic ectodermal dysplasia (HED). Symptoms include spare hair, defects in sweat glands activity, abnormal teeth and dystrophic nails. In the present study, whole-exome sequencing was performed to identify disease-causing variants in an Iranian 4-year-old affected boy with sparse hairs, low eyelashes and eyebrows, reduced teeth, severe dry skin, and reduced sweat glands. We confirmed the pathogenicity and its novelty within silico tools. Identifying variant confirmation in the patient and segregation analysis in her family were performed using the Sanger sequencing method. A novel hemizygous missense variant [NM_001399.5: c.1001G>C; p. (Arg334Pro)] was identified within the EDA gene; and this is the third case of HED in Iran that is related to the EDA gene. The distinction between our patient’s indications and those recorded for a few past subjects may be due to the differences in the mutations involved.

Keywords

Hypohidrotic Ectodermal Dysplasia

HED

WES

Novel Mutation

EDA

Ahmed HA, El-Kamah GY, Rabie E, Mostafa MI, Abouzaid MR, Hassib NF, Mehrez MI, Abdel-Kader MA, Mohsen YH, Zada SK, Amr KS, Sayed ISM. Gene Mutations of the Three Ectodysplasin Pathway Key Players (EDA, EDAR, and EDARADD) Account for More than 60% of Egyptian Ectodermal Dysplasia: A Report of Seven Novel Mutations. Genes. 2021; 12(9):1389.
Dorgaleleh S, Naghipoor K, Hajimohammadi Z, Oladnab M. Molecular basis of ectodermal dysplasia: a comprehensive review of the literature. Egypt J Dermatol Venereol. 2021; 41(2):55.
Dorgaleleh S, Toutounchi Z, Soltani M, Naghipoor K, Oladnabi M. The role of different genes in causing infection of ectodermal dysplasia patients: A systematic review. HBB. 2022; 5(4):86–104.
Cai Z, Deng X, Jia J, Wang D, Yuan G. Ectodysplasin A/Ectodysplasin A Receptor System and Their Roles in Multiple Diseases. Front Physiol. 2021; 12:788411.
Elomaa O, Pulkkinen K, Hannelius U, Mikkola M, Saarialho-Kere U, Kere J. Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein. Hum Mol Genet. 2001; 10(9):953–62.
Cui CY, Schlessinger D. EDA Signaling and Skin Appendage Development. Cell Cycle. 2006; 5(21):2477–83.
Tumminello M, Gangemi A, Matina F, Guardino M, Giuffrè BL, Corsello G. First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant? Ital J Pediatr. 2021; 47(1):128.
Martínez-Romero MC, Ballesta-Martínez MJ, López-González V, Sánchez-Soler MJ, Serrano-Antón AT, Barreda-Sánchez M, et al. EDA, EDAR, EDARADD and WNT10A allelic variants in patients with ectodermal derivative impairment in the Spanish population. Orphanet J Rare Dis. 2019; 14:281.
Song S, Han D, Qu H, Gong Y, Wu H, Zhang X, Zhong N, Feng H. EDA Gene Mutations Underlie Non-syndromic Oligodontia. J Dent Res. 2009; 88(2):126–31.
Kai Z, Kang YU, Feng W, Wei H, Yuan-yuan SUN, Yi-qun WU. Mutation screening and functional analysis for 8 patients with ectodermal dysplasia. Shanghai J Stomatol. 2019; 28(3):268.
Shen L, Liu C, Gao M, Li H, Zhang Y, Tian Q, Ni H, Peng P, Zhao R, Hu Z, Gao Y, Xia K, Bo O, Guo H. Novel mutation of EDA causes new asymmetrical X-linked hypohidrotic ectodermal dysplasia phenotypes in a female. J Dermatol. 2019; 46(8):731–3.
Ebadi N, Javadi S, Salmani T, Miryounesi M, Yassaee VR, Ghafouri-Fard S. Autosomal Recessive Hypohidrotic Ectodermal Dysplasia Caused by a Novel Mutation in EDAR Gene. Int J Pediatr. 2018; 6(1):6899–902.
Haghighi A, Nikuei P, Haghighi-Kakhki H, Saleh-Gohari N, Baghestani S, Krawitz P m., Hecht J, Mundlos S. Whole-exome sequencing identifies a novel missense mutation in EDAR causing autosomal recessive hypohidrotic ectodermal dysplasia with bilateral amastia and palmoplantar hyperkeratosis. Br J Dermatol. 2013; 168(6):1353–6.
Torkamandi S, Gholami M, Mohammadi-Asl J, Rezaie S, Zaimy MA, Omrani MD. A Novel Splicesite Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohydrotic (Anhidrotic) Ectodermal Dysplasia in an Iranian Family. Int J Mol Cell Med. 2016; 5(4):260–3.
Ghafouri-Fard S, Fardaei M, Tabei SMB, Dianatpour M, Miryounesi M. A CDH3 Mutation is segregated in an Iranian Family with Congenital Hypotrichosis and Juvenile Macular Dystrophy. Int J Pediatr. 2018]; 6(1):6999–7002.
Rahbaran M, Hassani Doabsari M, Salavitabar S, Mokhberian N, Morovvati Z, Morovvati S. A novel frameshift mutation in the EDA gene in an Iranian patient affected by X-linked hypohidrotic ectodermal dysplasia. Cell Mol Biol Lett. 2019; 24:54.
Papi A, Khatami S, Galehdari H, Shariati G. A Novel Missense Mutation in the EDAR Gene and One Missense Mutation in EDA Gene in the Study of HED Patients in Iran. Iran J Pediatr. 2021; 31(5).
Humbatova A, Maroofian R, Romano MT, Tafazzoli A, Behnam M, Dilaver N, Nouri N, Salehi M, Wolf S, Frank J, Kokordelis P, Betz RC. An insertion mutation in HOXC13 underlies pure hair and nail ectodermal dysplasia with lacrimal duct obstruction. Br J Dermatol. 2018; 178(4):e265–7.
Fallahi GH, Sabbaghian M, Khalili M, Parvaneh N, Zenker M, Rezaei N. Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur J Pediatr. 2011; 170(2):233–5.
Momen T, Alborzi A, Eslamian MH, Casanova JL, Picard C. First Case of X-linked Recessive Anhidrotic Ectodermal Dysplasia with Immunodeficiency from Iran with Unusual Aspergillus Infection. Immunol Genet J. 2019; 2:213–20.
Ghaderi F, Hekmat S, Ghaderi R, Fardaei M. MSX1 Mutation in Witkop Syndrome; a Case Report. Iran J Med Sci. 2013; 38(2 Suppl):191–4.
Eftekhariyazdi M, Meshkani M, Moslem A, Hakimi P, Safari S, Khaligh A, Zare-Abdollahi D. Ellis-van Creveld syndrome: Report of a case and recurrent variant. J Gene Med. 2020; 22(6):e3175.
Rajaee A, N N, M.h K, M.p L, R H, A K. Unusual Presentation Of Goltz Syndrome With Minimal Ectodermal Involvement In A 3-Year-Old Iranian Girl. Iran J Pediatr. 2014; 24(2):21–2
Saadat M, Ansari-Lari M, Farhud DD. Consanguineous marriage in Iran. Ann Hum Biol. 2004; 31(2):263–9.