Fanconi Anemia via the FANCE Gene

Fanconi Anemia (FA) is an inherited anemia associated with bone marrow failure (aplastic anemia), however, the clinical features of FA can expand well beyond hematologic anomalies. FA is also characterized by a range of physical abnormalities, pancytopenia, and predisposition to certain cancers - particularly acute myelogenous leukemia (AML), gynecologic and GI tract cancers, and cancers of the head and neck (Auerbach. 2009. PubMed ID: 19622403). FA patients are up to 800 fold more susceptible to AML than the general population with a median age of onset of 13 years (Rosenberg et al. 2003. PubMed ID: 12393424). Physical abnormalities include radial ray defects (absent thumb or radius), skin pigmentation defects, short stature, microphthalmia, renal and urinary tract defects, genital defects (males in particular), gastrointestinal malformations (atresia), congenital heart disease, hearing and central nervous system defects, and general developmental delay (Tischkowitz and Hodgson. 2003. PubMed ID: 12525534; Dokal. 2000. PubMed ID: 11030042). About one-third of FA patients have no obvious physical abnormalities and are diagnosed only after a family member is diagnosed, or after developing hematologic anomalies such as thromobocytopenia, leukopenia, and anemia (Giampietro et al. 1997. PubMed ID: 8986277).

A hallmark of FA is hypersensitivity of chromosomes to inter cross-strand linkage (ICL) agents such as diepoxybutane (DEB) or mitomycin C (MMC) (Sasaki and Tonomura. 1973. PubMed ID: 4352739). Exposure of primary cell cultures from FA patients to DEB or MMC results in chromosomal aberrations (breaks, radials, rearrangements) due to deficient DNA repair mechanisms that require functional products of the Fanconi anemia genes. For example, the FANCA, -B, -C, -E, -F, -G, -L, and -M proteins are part of a nuclear core complex that regulates monoubiquitination of the FANCD2 and FANCI proteins (ID complex) during S-phase and after exposure to DNA crosslinking agents (Moldovan and D'Andrea. 2009. PubMed ID: 19686080). In unaffected individuals, ubiquitination helps localize the ID complex to sites of DNA damage and facilitate repair, but in FA patients, this mechanism is impaired (Grompe and van de Vrugt. 2007. PubMed ID: 17488615; Smogorzewska et al. 2007. PubMed ID: 17412408).

FA is a genetically heterogeneous disorder. To date, 22 FA or FA-like genes have been discovered. Inheritance is primarily autosomal recessive or X-linked, however a case of heterozygous FA-like syndrome was associated with a dominant-negative variant in the RAD51 (FANCR) gene (Ameziane et al. 2015. PubMed ID: 26681308). Approximately 86% of all cases are attributed to variants in three genes: FANCA (~ 60%), FANCC (~ 16%), and FANCG (~ 10%) (Auerbach. 2009. PubMed ID: 19622403). Since variants in FANCA are the most common cause of FA, it is important to note that large deletions make up over one-third of all reported pathogenic variants in FANCA. In the United States, the carrier frequency for Fanconi anemia is estimated at 1 in 181, and the incidence rate is estimated at 1 in 131,000 (http://www.fanconi.org/; Rosenberg et al. 2011. PubMed ID: 21739583). Nearly 95% of all FA cases are attributed to variants in eight genes, FANCA, -C, -G, -D1 (aka BRCA2), -D2, -E, -F, and –L that are either part of the core complex required for ID complex ubiquitination and facilitation of DNA repair or function directly in ICL recognition and repair (Grompe and van de Vrugt. 2007. PubMed ID: 17488615). FA is phenotypically diverse even among related patients that harbor the same variants; null alleles however are reported to result in more severe phenotypes (Faivre et al. 2000. PubMed ID: 11110674). FA affects males and females roughly equally and affects all ethnic groups.

Around 20 unique variants in FANCE, consisting primarily of missense and nonsense variants, have been reported to cause autosomal recessive FA (https://databases.lovd.nl/shared/genes/FANCE). Variants in FANCE are estimated to account for ~ 3% of all FA cases (de Winter et al. 2000. PubMed ID: 11001585; Shimamura and Alter. 2010. PubMed ID: 20417588; Ameziane et al. 2008. PubMed ID: 17924555). Variants in the FANCE protein have been reported to alter DNA repair by failing to properly recruit FANCD2 protein to the FA E3 ligase complex (core complex) (Polito et al. 2014. PubMed ID: 24451376). Unlike other genes associated with the FA core complex, no multi-exon or whole gene deletions or duplications have been reported for the FANCE gene.

Pathogenic variants in the FANCE gene account for ~3% of all Fanconi anemia (FA) cases (Auerbach. 2009. PubMed ID: 19622403; Shimamura and Alter. 2010. PubMed ID: 20417588).

Unlike other genes associated with the FA core complex, no multi-exon or whole-gene deletions or duplications have been reported for the FANCE gene (The Rockefeller University Fanconi Anemia Mutation Database; Human Gene Mutation Database).

This test provides full coverage of all coding exons of the FANCE gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).