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. 2023 May 31:14:1170449.
doi: 10.3389/fendo.2023.1170449. eCollection 2023.

The prevalence and genotype of 21-hydroxylase deficiency in the Croatian Romani population

Katja K Dumic  1 , Zorana Grubic  2 , Vesna Kusec  3 , Duje Braovac  1 , Kristina Gotovac  4 , Maja Vinkovic  1 , Maja Vucinic  5 , Miroslav Dumic  1
Affiliations

The prevalence and genotype of 21-hydroxylase deficiency in the Croatian Romani population

Katja K Dumic et al. Front Endocrinol (Lausanne). .

Abstract

Objective: Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency (21-OHD) is a rare autosomal recessive disorder caused by pathological variants in the CYP21A2 gene. After a high prevalence of classic 21-OHD CAH in the Romani population was reported in the Republic of North Macedonia, we decided to estimate the prevalence of 21-OHD in Croatia and, if high, assess the possible causes and estimate the frequency of particular CYP21A2 variants.

Design: Cross-sectional study.

Methods: Data from a Croatian 21-OHD genetic database was reviewed, and only Romani patients were included in the study. CYP21A2 genotyping was performed using allele-specific PCR, MLPA, and Sanger sequencing.

Results: According to a survey conducted in 2017, Croatia had 22,500 Romani people and six of them had a salt-wasting (SW) form of 21-OHD. All were homozygous for the c.IVS2-13A/C-G pathological variant in intron 2 and descended from consanguineous families belonging to different Romani tribes. The calculated prevalence of 21-OHD in Croatian Romani is 1:3,750, while in the Croatian general population, it is 1:18,000. Three of the six Romani patients originated from two neighboring villages in North-western Croatia (Slavonia County), as well as the seventh patient who is of mixed Romani/Croatian descent and heterozygous for the c.IVS2-13A/C-G pathological variant (not included in the prevalence calculation).

Conclusion: A high prevalence of SW 21-OHD in the Croatian Romani population caused by the homozygous cIVS2-13A/C-G pathological variant was found. In addition to isolation and consanguinity, other possible reasons could be the heterozygous advantage of the CYP21A2 gene pathological variant and the bottleneck effect as a result of the Romani Holocaust in World War II.

Keywords: CYP21A2 heterozygous advantage; Romani Holocaust; Romani tribes; bottle neck effect; congenital adrenal hyperplasia; consanguinity; founder mutation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pedigrees and genotypes of the six Romani patients and one mixed Romani/Croatian patient with classical congenital adrenal hyperplasia due to 21-OH deficiency. N.t., not tested; N, pathological variant in the CYP21A2 gene not found.
See this image and copyright information in PMC

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