Somatic mosaicism in inherited bone marrow failure and chromosomal instability syndrome

Abstract

Chromosomal instability syndromes (CIS) show autosomal recessive inheritance patterns and are identified by breakage of the chromosome and chromosomal instability which are mostly direct results of DNA repair machinery defects that lead to many phenotypic manifestations including an increased predisposition to malignancies. The most commonly known CIS are Fanconi anaemia (FA), Nijmegen syndrome (NS), Bloom’s syndrome (BS), Ataxia-telangiectasia (A-T) and Ataxia telangiectasia like disorder (ATLD). Inherited bone marrow failure syndromes constitute a group of diseases that are extremely rare and can be described by inadequate blood cell production of single or multiple hematopoietic lineages. A major proportion of IBMFs is caused by defective genes that are involved in cellular pathways like ribosome function, telomere biology, transcription regulation, DNA repair, and telomere maintenance. In these diseases, bone marrow failure is frequently linked to other somatic abnormalities. IBMFS includes disorders such as Thrombocytopenia absent radii, Congenital amegakaryocytic thrombocytopenia and Fanconi anemia. The clinical phenotypes of these diseases are often overlapping and hence proper and accurate diagnosis is a challenge. Moreover, these diseases show great clinical heterogeneity and disease penetrance which can be explained to some extent by somatic mosaicism. Mosaicism can be a result of several mutations that have proliferated to only a small cluster of adult cells during the early developmental stages of the organism and subsequently during aging. The tissues in the body of an individual are regularly subjected to several intrinsic and extrinsic mutagenic stresses which can result in the accumulation of many genetic variations ranging from single base pair to ploidy level changes. During the past decades, somatic mosaicism has emerged as one of the major contributing factors in many monogenic disorders. These disorders are often associated with a predisposition to cancer, therefore, early and proper diagnosis is extremely important for adequate management and treatment.