Fanconi Anemia via the RAD51C/FANCO Gene

Fanconi anemia (FA) is considered a blood disorder, however the clinical features of FA expand well beyond hematologic disorders alone. FA is characterized by a range of physical abnormalities, bone marrow failure (aplastic anemia), pancytopenia, and predisposition to cancers—particularly acute myelogenous leukemia (AML), gynecologic and GI tract cancers, and cancers of the head and neck (Auerbach. Mutat Res 668:4-10, 2009). 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. Blood 101:822, 2003). 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. J Med Genet 40:1-10, 2003; Dokal. Baillieres Best Pract Res Clin Haematol 13:407-425, 2000). 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. Am J Med Genet 68:58-61, 1997). A hallmark of FA is hypersensitivity of chromosomes to interstrand cross linking agents such as diepoxybutane (DEB) or mitomycin C (MMC; Sasaki and Tonomura. Cancer Res 33:1829-1836, 1973). Exposure of primary cell cultures from FA patients to DEB or MMC results in chromosomal abberations (breaks, radials, rearrangements) due to damaged 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. Annu Rev Genet 43:223, 2009). In unaffected individuals, ubiquitination helps localize the ID complex to sites of DNA damage and facilitate repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007; Smogorzewska et al. Cell 129:289, 2007), but in FA patients, this mechanism is impaired.

FA is a genetically heterogeneous autosomal recessive disorder. To date, 16 FA or FA-like genes have been discovered. Approximately 86% of all cases are attributed to variants in three genes: FANCA (~60%; OMIM 607139), FANCC (~16%; OMIM 227645), and FANCG (~10%; OMIM 602956; Auerbach. Mutat Res 668:4-10, 2009). Nearly 95% of all cases are attributed to variants in the eight genes, FANCA, -B, -C, -E, -F, -G, -L, and -M, that encode components of a nuclear core complex required for ID complex ubiquitination and facilitation of DNA repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007). In the United States, the carrier frequency for FA is estimated at 1 in 181 and the incidence rate of FA is estimated at 1 in 131,000 (http://www.fanconi.org/; Rosenberg et al. Am J Med Genet A 155:1877, 2011). With the exception of FANCD1 and FANCN patients who seem to have more severe clinical symptoms, obvious genotype-phenotype correlations are lacking, and related individuals who harbor a common variant(s) may have drastically different phenotypes. The FA-like phenotype includes severe congenital abnormalities and positive chromosomal breakage tests common to FA but is considered FA-like because no indication of bone marrow failure or tumor development has yet been observed in the index family (Vaz et al. Nat Genet 42:406, 2010). Variants in RAD51C account for a very small fraction of FA or FA-like cases. To date, only one variant in the RAD51C gene, c.773G>A (p.Arg258His) has been associated with the FA-like phenotype (Vaz et al. Nat Genet 42:406, 2010). However, several other monoallelic variants in the RAD51C gene have been linked to hereditary breast and ovarian cancer (Meindl et al. Nat Genet 42:410, 2010) thereby identifying RAD51C as a cancer susceptibility gene.

Variants in known FA genes are found in >95% of cases. RAD51C variants are a rare cause of FA.

This test provides full coverage of all coding exons of the RAD51C gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.