Fanconi Anemia Founder Mutation in Macedonian Patients

Abstract

Background: Fanconi anemia (FA) is a rare autosomal recessive disorder clinically characterized by developmental abnormalities, progressive bone marrow failure (BMF) and profound cancer predisposition. Approximately 65% of all affected individuals have mutation in the FANCA (Fanconi anemia complementation group A) gene. The mutation spectrum of the FANCA gene is highly heterogeneous. FA-A is usually associated with private FANCA mutations in individual families. Methods: We describe 3 unrelated patients with FA with a similar clinical presentation: BMF, renal anomalies and café-au-lait pigmentation without major skeletal abnormality. The molecular analysis of the FANCA gene using the FA MLPA kit P031-A2/P032 FANCA, showed homozygous deletion of exon 3 in all 3 patients. Molecular analysis of the flanking regions of exon 3 precisely defined unique deletion of 2,040 bp and duplication of C (1788_3828dupC). Discussion/Conclusions: These are the first 3 patients homozygous for deletion of FANCA exon 3 described to date. Although not related, the patients originated from the same Gypsy-like ethnic population. We conclude that c.190-256_283 + 1680del2040 dupC mutation in the FANCA gene is a founder mutation in Macedonian FA patients of Gypsy-like ethnic origin. Our finding has very strong implications for these patients in formulating diagnostic and carrier-screening strategy for BMF and FA and to enable comprehensive genetic counseling.

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

“…Kalb and colleagues also found that some FANCD2 mutations are highly specific for the patients' origin, such as splice mutation in intron 21, c.1948-16 T>G which is strongly related to the Turkish origin (KALB et al, 2007). Association of specific mutations with the certain populations was also found in other FA genes (MADJUNKOVA et al, 2014;TIPPING et al, 2001). Variants in intron 3, c.206-246 delG and exon 26, c.2396 C>A, found in this study, were not previously reported, even though large-scale studies on FA-D2 patients from multiple populations have been performed, indicating their possible linkage to the Serbian population.…”

Novel Founder Mutation in FANCA Gene (c.3446_3449dupCCCT) Among Romani Patients from the Balkan Region

“…Genomic DNA was obtained from peripheral blood of the probands and their parents. Due to a suspicion of FA, the patients were screened for the known Macedonian founder mutation, c.190–256_283+1680del2040dupC (exon 3 deletion) in the FANCA gene, as already described ( 6 ). This mutation was only detected in patient 1 and her mother in a heterozygous state.…”

“…Furthermore, mutations that recur in one ethnic population have also been described. Recently, we have shown that FANCA c.190–256_283+1680del2040dupC is a founder mutation in Macedonian FA patients of Gypsy-like ethnic origin ( 6 ).…”

Genetics in Macedonia—Following the international trends

“…In the field of immunogenetics, a series of studies have been published in well-known journals (Petlichkovski et al, 2004(Petlichkovski et al, , 2011Petlickovski et al, 2005;Spiroski et al, 2013). The research studies published by the Research Center for Genetic Engineering and Biotechnology regarding the molecular diagnostics of many monogenetic diseases and chromosomal disorders are numerous, some describing unique genetic variants (Efremov, Dimovski, & Huisman, 1994;Efremov et al, 1988Efremov et al, , 1996Madjunkova, Kocheva, & Plaseska-Karanfilska, 2014; Dimovski AJ, A large beta-thalassemia deletion in a family of Indonesian-Malay descent., 1996; Plaseska et al, 1990).…”