FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients

Abstract

Fanconi anemia (FA), a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C). Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions.

FANCA and contribution of studies from Asian populations to the understanding of fanca mediated Fanconi anemia

“…Out of these 26 mutations 7 were missense of which three(3/7;43%) were novel i.e., c.3679C>G (p.Ala1227Pro), c.1273C>G (p.Asp425His), c.3992T>C (p.Leu1331Pro) and (5/7; 57%) were already reported from Netherlands (AMEZIANE et al, 2008), Japan (TACHIBANA et al, 1999b;ADACHI et al, 2002;YAGASAKI et al, 2004b), Brazil (LEVRAN et al, 1997 and USA populations (CHANDRA et al, 2005a;LEVRAN et al, 2005b). The c.2851C>T mutation in exon 29 is highly predominant in India (SOLANKI et al, 2016), Netherlands (AMEZIANE et al, 2008, and USA (CHANDRA et al, 2005a;LEVRAN et al, 2005b). In addition, c.2574C>G mutation in exon 27 is highly prevalent in India (SOLANKI et al, 2016), Netherlands (WIJKER et al, 1999a), Israeli (TAMARY et al, 2000TAMARY et al, 2004a) populations and c.1303C>T in exon14 is highly dominant in India (SOLANKI et al, 2016), Japan (TACHIBANA et al, 1999b;ADACHI et al, 2002;YAGASAKI et al, 2004b), andBrazil (LEVRAN et al, 1997).…”

“…The most common mutation was 2546delCin exon 27 which was present in six out of 15 patients (40%), resulting in a premature termination codon 40 codons downstream and formation of a truncated protein of 887 amino acids (TACHIBANA et al, 1999b). Among the other base substitutions, 1303C>T pathogenic missense mutation was found in 12 out of 15 analyzed FA patients (80%) and has reported higher incidence in Indian (SOLANKI et al, 2016) and Brazilian FA patients as well . Another report by Adachi and his group also described some FANCA mutations but those were previously reported by Levran et al, 2005) (see Table 1) (ADACHI et al, 2002).…”

“…Most recently Solanki, et al (2016) studied 550-FA suspected adults and children (SOLANKI et al, 2016). After chromosomal breakage test, 61 confirmed cases with FA were subjected to MLPA analysis and direct sequencing.…”

“…After chromosomal breakage test, 61 confirmed cases with FA were subjected to MLPA analysis and direct sequencing. A total of 26 FANCA variations were identified in 34 unrelated individual of which 8 were novel mutations and remaining were previously reported (SOLANKI et al,. 2016).…”

“…The c.2851C>T mutation in exon 29 is highly predominant in India (SOLANKI et al, 2016), Netherlands (AMEZIANE et al, 2008, and USA (CHANDRA et al, 2005a;LEVRAN et al, 2005b). In addition, c.2574C>G mutation in exon 27 is highly prevalent in India (SOLANKI et al, 2016), Netherlands (WIJKER et al, 1999a), Israeli (TAMARY et al, 2000TAMARY et al, 2004a) populations and c.1303C>T in exon14 is highly dominant in India (SOLANKI et al, 2016), Japan (TACHIBANA et al, 1999b;ADACHI et al, 2002;YAGASAKI et al, 2004b), andBrazil (LEVRAN et al, 1997). Among 6 nonsense mutations identified in this study, 4 were new c.2182C>T, c.2630C>G, c.3189G>A and c.3677C>G in exon 24, 28, 32, 37 respectively.…”