Molecular Characterization of a Prototype Family Harboring Two Genomic Instability Disorders: Ataxia Telangiectasia and Fanconi Anemia.
Authors: Balta Gunay , Patiroglu Turkan , Gumruk Fatma , Sanal Ozden , Gurgey Aytemiz , Altay Cigdem 
Published: October 2019

Abstract
Ataxia telangiectasia (AT) and Fanconi anemia (FA) are rare, clinically distinct autosomal recessive disorders characterized by genomic instability and predisposition to cancer. In recent years, it was demonstrated that ATM and FA genes function in parallel and interrelate in DNA damage response pathways to maintain genomic integrity and cell viability. To date, no case or a family with these two genomic instability disorders with proven genetic defects, clinical and laboratory features has been reported. In this study, we characterize the molecular pathologies of a prototype family exceptionally harboring both AT and FA patients. Among the 5 ofsprings of a consanguineous parents of first degree cousin marriage, 1 male was diagnosed as AT, 1 male and 1 female as FA, 1 male and 1 female appeared to have none of these two disorders. Family history revealed that a 1.5 years old female child was deceased, and the mother had 1 early abortion and 1 intrauterine death at the 8th months of pregnancy. During the follow up period of 5 years, the patient with AT and the male patient with FA were lost due to the complications of the related disorders. Linkage analysis of DNA samples of the family members for FA led to the assignment of the family to complementation group A. The mutation analysis of 43 exons of FANCA gene revealed novel homozygous co-deletions of 10 (1361–1370del) and 1 (1374delC) nucleotides at the 5′ end of exon 15 leading to 3 aminoacid deletions and frameshift. Screening of the family members for the mutation revealed that 2 FA patients were homozygous and the parents and the patient with AT were heterozygous for the mutation while other 2 siblings were non-carriers for FA. The mutation was not detected among 200 chromosomes from normal population. On the other hand, linkage analysis of the family for AT with the intra ATM gene microsatellite markers showed that AT patient was homozygous while other family members were heterozygous for the common haplotype observed in parents. In this patient, sequencing of the 62 coding exons of the ATM gene led to the identification of a homozygous C to T substitution (8977C>T) at exon 61. This alteration resulted in replacement of Arginin with termination at codon 2993 (R2993X) leading to 63 aminoacid truncation of the ATM protein. Consistent with the linkage results, all the other family members including 2 FA patients were heterozygous for the mutation. The results of this study showed that the state of homozygosity for AT with a coexistent heterozygosity for FA or homozygosity for FA with a coexistent heterozygosity for AT are compatible with life. This observation indicates that even in the presence of null mutations, such combinations do not alter phenotypic expression of the homozygous states of neither AT nor FA. However, in this family with 5 living siblings, absence of any case coinciding homozygous mutations for both disorders may indicate that such possibilities are not compatible with life. Even though there is no laboratory evidence due to absence of fetal study, presence of maternal history of an abortion and an intrauterine death may be considered as evidences in supporting assumption above.