Analysis of FANCC gene mutations (IVS4+4A>T, del322G, and R548X)in patients with Fanconi anemia in Pakistan

Abstract

Background/aim: Fanconi anemia (FA) is an autosomal recessive disease determined by mutations in at least 16 genes, with distinct distributions in different populations. To the best of our knowledge, there are no reports regarding the molecular basis of the disease in FA patients in Pakistan. The current study aimed to determine the frequency of FANCC gene mutations, i.e. IVS4+4A>T, del322G, and R548X, in FA patients.Materials and methods: Genomic DNA was obtained from 36 FA patients. All samples were analyzed by polymerase chain reaction and restriction fragment length polymorphism techniques.Results: Mutation IVS4+4A>T was identified in 26 (72.2%) patients. It was homozygous in 6 and heterozygous in 20 patients. Del322G and R548X were found with the following prevalences: del322G, 5.6%, and R548X, 5.6%. Patients with these two mutations were compound heterozygotes having concomitant IVS4+4A>T mutation. Conclusion:These results suggest that mutation IVS4+4A>T is the most prevalent mutation in our group of patients. This analysis of Pakistani patients also suggests that there is no significant difference between IVS4+4A>T homozygotes and the rest of the patients with regard to severity of clinical phenotype.

Five Novel Deleterious Variants in FANCA, FANCF and FANCG Identified in Pakistani Fanconi Anemia Families Using Exome Sequencing

“…However, the presence of homozygous pathogenic variants in our data is consistent with prior studies reporting an approximately 70% rate of consanguineous marriages in Pakistan (66)(67)(68). Nine of the 14 pathogenic variants identi ed have been previously reported (Table 2) (12,(14)(15)(16)(17)(18).…”

“…Relatedness analyses determined that these probands were from distinct families. FANCC p.Arg548* (rs104886457, ClinVar:12047) has been previously reported in two FA patients from Pakistan (16).…”

The causes of Fanconi anemia in South Asia and the Middle East: A case series and review of the literature

“…There have been a limited number of reports on the genetic etiology of FA in populations from South Asia and the Middle East. Such studies have identified several novel disease‐causing germline genetic variants, including the first reports of FA caused by pathogenic variants in FANCO / RAD51C or FANCE (Aftab et al, 2017 ; Aslan et al, 2015 ; Aymun et al, 2017 ; Balta et al, 2000 ; Castella et al, 2011 ; de Winter et al, 2000 ; Donovan et al, 2019 ; Dorsman et al, 2007 ; Esmail Nia et al, 2016 ; Ghazwani et al, 2016 ; Gille et al, 2012 ; Kalb et al, 2007 ; Koc et al, 1999 ; Levran et al, 1997 ; Moghadam et al, 2016 ; Salem et al, 2014 ; Shahid et al, 2019 ; Shamseldin et al, 2012 ; Shukla et al, 2013 ; Solanki et al, , 2016 , 2017 ; Tamary et al, , 2000 , 2004 ; Vaz et al, 2010 ; Vundinti, 2014 ; Waisfisz et al, 1999 ; Wegner et al, 1996 ; Wijker et al, 1999 ; Zareifar et al, 2019 ) as well as discovery of a founder mutation in FANCL (Donovan et al, 2019 ), highlighting the importance of germline genetic studies of FA in underrepresented regions. In this report, we evaluated the genetic causes of FA in 19 patients from 17 unrelated families being considered for HCT in Pakistan and conducted a detail review of the causes of FA in South Asia and the Middle East.…”

Screening for mutations in two exons of FANCG gene in Pakistani population

“…Researchers from our institution have already worked on FANCA and FANCC genes. Their work has shown FANCA mutations in 47% of patients and FANCC in 72% of patients 38 . So we decided to take up the third most prevalent gene i.e., FANCG.…”