A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families

Abstract

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA-null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype-phenotype correlations.

A founder variant in the South Asian population leads to a high prevalence ofFANCLFanconi anemia cases in India

“…FA is a genetically heterogeneous disorder (Kimble et al, ), but even amidst the genetic diversity observed among FA patients, high‐frequency pathogenic variants in FA genes influenced by a founder effect have been identified among genetically isolated populations. But, to date, these variants were limited to the more common FA genes.…”

Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report

“…There are two main repair pathways for double-strand breaks: nonhomologous end joining and homologous recombination. FANCA belongs to the Fanconi anemia complementation group (FANC) family and is known as one of the genes responsible for Fanconi anemia [7]. It plays an important role in DNA interstrand crosslinking in homologous recombination repair [8].…”

Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

“…Fanconi anemia (FA) is a rare genetic disease highly heterogeneous in clinical manifestations and genetics. Clinical manifestations primarily include congenital malformations, progressive bone marrow failure (BMF), and predisposition to hematopoietic and solid malignancies [1,2]. The most common congenital abnormalities include skin pigmentation, café au lait spots, short stature, and hypoplastic of radii and/or thumbs [2].…”