Fanconi Anemia via the PALB2/FANCN 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 the 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 aberrations (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 the three genes FANCA (OMIM 607139) (~ 60%), FANCC (OMIM 227645) (~ 16%), and FANCG (OMIM 602956) (~ 10%) (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. Numerous variants are found throughout the PALB2/FANCN gene and include some missense and splicing variants but primarily include nonsense variants and other small insertions and deletions that result in premature termination (http://www.rockefeller.edu/fanconi/genes/). In relation to other FA patients, FA-N patients often develop leukemia at an earlier age, show increased spontaneous chromosomal breakage, and develop solid tumors (medulloblastoma, astrocytoma, and Wilms Tumors) that are rarely seen in other FA patients (Reid et al. Nat Genet 39:162-164, 2007). In addition, monoallelic variants in PALB2/FANCN predispose to adult cancers, particularly breast cancer, and PALB2/FANCN should be considered among the cancer susceptibility genes (Rahman et al. Nat Genet 39:165, 2007; Tischkowitz et al. PNAS 104:6788, 2007).

Variants in FA genes account for >95% of all patients with FA.

This test provides full coverage of all coding exons of the PALB2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.