Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia

Abstract

Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene. Affected individuals manifest severe congenital anomalies and significant pigmentary changes and are additionally at risk for early onset leukemia and certain solid organ malignancies, including Wilms tumors and brain tumors. Parents of affected individuals are obligate carriers for heterozygous BRCA2 mutations and are thus potentially at risk for adult onset cancers which fall within the hereditary breast and ovarian cancer spectrum. We present two cases of black South African patients with FA diagnosed with biallelic BRCA2 mutations and discuss the phenotypic consequences and implications for them and their families. Recognition of this severe end of the phenotypic spectrum of FA is critical in allowing for confirmation of the diagnosis as well as cascade screening and appropriate care of family members.

Essential Role ofBRCA2in Ovarian Development and Function

“…18 Descriptions of fertility problems in patients with Fanconi’s anemia D1 (who carry pathogenic variants in both copies of BRCA2 ) are lacking, because patients described in previous reports did not survive past childhood. 23–27…”

Essential role of BRCA2 in ovarian development and function

“…18 Descriptions of fertility problems in patients with Fanconi's anemia D1 (who carry pathogenic variants in both copies of BRCA2) are lacking, because patients described in previous reports did not survive past childhood. [23][24][25][26][27] Our results indicate that ovarian development depends on the normal repair of doublestranded DNA breaks that occur at recombination during meiosis. These results highlight an emerging concept of a critical role for DNA repair genes (e.g., MCM-8, 2 MCM-9, and, as we report here, BRCA2) in ovarian development and function.…”

Fanconi anaemia in South Africa: Past, present and future

“…[11,17] The more recent discovery that BRCA1 (FANCU) and BRCA2 (FANCD1), implicated in the causation of hereditary breast and ovarian cancer syndrome (HBOC), are also part of the FA pathway highlights the interplay between abnormal DNA repair mechanisms and the evolution of cancer. [11,18] Most of the FA genes exhibit mutational or allelic heterogeneity, which is evidenced by the large number of sequence variants and mutations that have been described, particularly in the FANCA and FANCG genes. [19][20][21] In >80% of black patients with FA, a homozygous seven basepair deletion mutation in the FANCG gene (NM_004629.1 g.35077270_35077264del p.Tyr213Lysfs) [2] has been confirmed as the cause of the disease.…”

“…[22] The molecular aetiology for the so-called 'G-negative' black patients with a clinical and/or cytogenetic diagnosis of FA is poorly understood, although most recently mutations in rarer FA genes, including BRCA2, have been identified. [18] In SA individuals with Afrikaner ancestry, three mutations in FANCA have been shown to account for ~80% of FA cases. [3] A founder mutation described in individuals of Ashkenazi Jewish ancestry is also found in SA individuals of this origin.…”

“…[31][32][33][34] A case report on two black SA children with FA in whom biallelic BRCA2 mutations were identified (Table 3) highlights the difficulties in care and management of these families, in that the children had severe anomalies associated with their FA phenotype, while the parents are obligate heterozygote carriers of a BRCA2 fault and receive an obligatory diagnosis of HBOC. [18] HBOC is associated with variable risks for breast, ovarian, prostate and pancreatic cancers as well as melanomas. [34] Solid-tumour risk for carriers of other rare FA genes, including FANCN (PALB2) and FANCO (RAD51C), is established in cohorts of patients with breast and/or ovarian cancer, with increased risks for breast cancer (33 -58% in PALB2) [35] and ovarian cancer (≤9% in RAD51C).…”