A Homozygous Germ Line Nonsense Mutation in BRCA1 Leading Fanconi Anemia and Neuroblastoma
Authors: Mehmet Demirel , Unal Sule , Gumruk Fatma , Akarsu Nurten Ayse 
Published: October 2019

Abstract
BRCA1 and BRCA2 play critical roles in maintenance of genomic integrity, DNA repair, and cell cycle checkpoint control. Deficiency in BRCA-associated DNA interstrand crosslink (ICL) repair is connected to breast cancer susceptibility and Fanconi anemia (FA) which is an autosomal recessive disorder that causes genomic instability along with abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. Homozygous or compound heterozygous mutations in the BRCA2 gene are well associated to severe FA phenotype (FANCD1) and solid tumor development. However, biallelic mutations in BRCA1 are extremely rare suggesting that most combinations of deleterious BRCA1 mutations might be lethal. In this study using whole exome sequencing we report the first homozygote nonsense BRCA1 mutation associated with Fanconi anemia in a three generation Turkish consanguineous family.
The afected individual is a five year-old girl who was diagnosed to have stage IV neuroblastoma at the age of two and treated uneventfully, in addition to a surgical intervention for ASD and VSD. During the follow-up she was diagnosed to have FA. Spontaneous chromosamal breakages were high, despite normal MMC and DEB. The physical examination revealed, microcephaly, short stature, microphtalmia, cafe-au-lait spots. Hb 11.2 g/dl, MCV 87.5 fl, WBC: 4.3x109/L and platelets 130 x109/L. She had received no transfusions except for the those during the chemotherapy for neuroblastoma treatment. Growth hormone deficiency was found. Cranial MRI exhibited widespread gliosis areas and prominences in the cerebral cortical sulci. Her elder brother was 13 years-old at the diagnosis. The physical examination revealed mental retardation, microcephaly, microphtalmia, cafe-au-lait spots and undescended testis. Small kidneys and periventricular and subcortical gliotic areas and central adrenal insufficiency were identified. Spontaneous chromosomal breakages were high and further increased with DEB. Both parents and two other siblings were healthy although uterus Ca, esophagus Ca and lung Ca were detected in family members in the history.
A homozygous stop codon mutation in exon 10 of BRCA1 gene, c.1151T>G/ p.Leu384Stop was identified in the whole exome study using Illumina HiSeq 2000 platform. Both afected individuals were homozygote and the mother was heterozygote fort his mutation DNA of the healthy father of affected siblings was not available.
To the best of our knowledge there are only two reports that compound heterozygote mutations in BRCA1 causes FA-like subtype (FANCS) (Domchek et al., Cancer Discov. 2013; 3:399-405 and Sawyer et al., Cancer Discov 2015; 5:135-142). In these reports, the patients do not display bone marrow failure, mutation carriers have higher risk of breast and ovarian tumors and lower onset age. However, one of the siblings in our report had mild thrombocytopenia. Also compatible with the previous report, our patients had intellectual disability. Interestingly, one of the siblings in our series had neuroblastoma and family members had uterus, esophagus and lung cancers. Our findings clearly show that homozygous deletorious BRCA1 mutations are vital and molecular analysis expands the spectrum of phenotypes associated with BRCA1 mutations.

Disclosures
No relevant conflicts of interest to declare.