High frequency of exon 15 deletion in the FANCA gene in Tunisian patients affected with Fanconi anemia disease: implication for diagnosis

Abstract

Tunisian population is characterized by its heterogeneous ethnic background and high rate of consanguinity. In consequence, there is an increase in the frequency of recessive genetic disorders including Fanconi anemia (FA). The aim of this study was to confirm the existence of a founder haplotype among FA Tunisian patients and to identify the associated mutation in order to develop a simple tool for FA diagnosis. Seventy-four unrelated families with a total of 95 FA patients were investigated. All available family members were genotyped with four microsatellite markers flanking FANCA gene. Haplotype analysis and homozygosity mapping assigned 83 patients belonging to 62 families to the FA-A group. A common haplotype was shared by 42 patients from 26 families at a homozygous state while five patients from five families were heterozygous. Among them, 85% were from southern Tunisia suggesting a founder effect. Using multiplex ligation-dependent probe amplification (MLPA) technique, we have also demonstrated that this haplotype is associated with a total deletion of exon 15 in FANCA gene. Identification of a founder mutation allowed genetic counseling in relatives of these families, better bone marrow graft donor selection and prenatal diagnosis. This mutation should be investigated in priority for patients originating from North Africa and Middle East.

Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes

“…Although the majority of pathogenic variants associated with FA are private germline variants, a few common founder mutations have been reported [Whitney et al, 1993;Tipping et al, 2001;Auerbach et al, 2003;Callen et al, 2005;Morgan et al, 2005;Castella et al, 2011;de Vries et al, 2012;Amouri et al, 2014]. Most of the founder mutations were identified after extensive sequencing efforts and haplotype analysis of populations with a high prevalence of disease, and are primarily SNV and INDELs.…”

Founder Haplotype Analysis of Fanconi Anemia in the Korean Population Finds Common Ancestral Haplotypes for a FANCG Variant

“…For example, the Manitoba Mennonite FA-C patients with c.67delG shared the same haplotype surrounding this mutation, indicating a common founder descended from the common Dutch ancestor (de Vries et al, 2012). The presence of ancestral FA mutations also supports the genetic homogeneity of the peoples in the same linguistic area, even though they live in diverse geographic areas or have different tribal origins (Morgan et al, 2005;de Vries et al, 2012;Amouri et al, 2014). The prevalence rate of FA in ethnic groups with a founder haplotype can be estimated by investigating its carrier frequency in unrelated controls (Morgan et al, 2005).…”

“…The genealogical investigation into the ancestors of the FA patients who carried the same haplotype enables us to estimate the mutation age and geographic origin of a common ancestor (Tipping et al, 2001;Morgan et al, 2005;de Vries et al, 2012;Amouri et al, 2014). For example, the Manitoba Mennonite FA-C patients with c.67delG shared the same haplotype surrounding this mutation, indicating a common founder descended from the common Dutch ancestor (de Vries et al, 2012).…”

“…The number of different pathogenic variants described for the FANCA gene is very high considering the relatively low number of patients (Wijker et al, 1999;Levran et al, 2005). Meanwhile, the incidence of FA is much higher due to a high degree of consanguinity, genetic isolation, or a founder effect in some ethnic groups, including the Ashkenazi Jews (Kutler & Auerbach, 2004), Moroccan Israeli Jews (Tamary et al, 2000), Germans , some clusters of Italian Gypsies (Savoia et al, 1996), the Spanish Gypsies (Callen et al, 2005), Macedonians (Madjunkova et al, 2014), Tunisians (Bouchlaka et al, 2003;Amouri et al, 2014), Japanese (Tachibana et al, 1999;Yagasaki et al, 2004), and the Afrikaner population of South Africa (Tipping et al, 2001). In addition, FANCC c.456+4A>T is well known as a founder mutation in the Ashkenazi Jewish population (Verlander et al, 1994(Verlander et al, , 1995.…”

Whole exome sequencing reveals a combination of rare high and low penetrance variants that correlates with familial breast cancer relative risk

“…Combination of rare pathogen variants in DNA repair genes with high or low penetrant variants in BRCA genes among Tunisian breast cancer cases might explain the relatively young onset age and the aggressive tumor types observed in some cases described in local epidemiological reports. Our previous studies have shown a relatively high rate of consanguinity 74,75 that increases the frequency of monogenic diseases such autosomal recessive DNA repair disorders predisposing to cancer and raise the prevalence of healthy carriers 76,77 ; (Ben Rekaya unpublished data).…”