Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children

Aisha Tolba; Iman Mandour; Noha Musa; Fatma Elmougy; Mona Hafez; Sahar Abdelatty; Amany Ibrahim; Hend Soliman; Bahaaeldin Labib; Yasmine Elshiwy; Tarek Ramzy; Marwa Elsharkawy

doi:10.3389/fgene.2022.785570

Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children

Front Genet. 2022 Mar 2:13:785570. doi: 10.3389/fgene.2022.785570. eCollection 2022.

Authors

Affiliations

¹ Clinical and Chemical Pathology Department, Cairo University, Giza, Egypt.
² Diabetes, Endocrine and Metabolism Pediatric Unit, Cairo University, Giza, Egypt.
³ Royal College of Surgeons in Ireland, Medical University of Bahrain, Giza, Egypt.

Abstract

Background: Congenital adrenal hyperplasia (CAH) is a monogenic disorder caused by genetic diversity in the CYP21A2 gene, with 21-hydroxylase deficiency (21-OHD) as the most common type. Early sex assignment and early diagnosis of different genetic variations with a proper technique are important to reduce mortality and morbidity. Proper early sex identification reduces emotional, social, and psychological stress. Aim: Detection of a spectrum of aberrations in the CYP21A2 gene, including copy number variations, gene conversion, chimeric genes, and point variations. Methods: The CYP21A2 gene was screened using MLPA assay in 112 unrelated Egyptian children with 21-OHD CAH (33 males and 79 females). Results: In the studied group, 79.5% were diagnosed within the first month of life. 46.8% of the genetic females were misdiagnosed as males. Among the copy number variation results, large deletions in 15.4% and three types of chimeric genes in 9% (CH-1, CH-7, and CAH-X CH-1) were detected. Regarding gene dosage, one copy of CYP21A2 was found in 5 cases (4.5%), three copies were detected in 7 cases (6.3%), and one case (0.9%) showed four copies. Eight common genetic variants were identified, I2G, large deletions, large gene conversion (LGC), I172N, F306 + T, -113 SNP, 8bp Del, and exon 6 cluster (V237E and M239K) with an allelic frequency of 32.62%, 15.45%, 7.30%, 3.00%, 2.58%, 2.15%, 0.86%, and 0.86%, respectively. Conclusion: High prevalence of copy number variations highlights the added value of using MLPA in routine laboratory diagnosis of CAH patients.

Keywords: 21-Hydroxylase deficiency; CYP21A2; congenital adrenal hyperplasia; copy number variations; multiplex ligation-dependent probe amplification.