Germline, hematopoietic, mosaic, and somatic variation: interplay between inherited and acquired genetic alterations in disease assessment
© The Author(s). 2016
Published: 5 October 2016
Advances in
Germline, hematopoietic, mosaic, and somatic variation: interplay between inherited and acquired genetic alterations in disease assessment
© The Author(s). 2016
Published: 5 October 2016
Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Correct assessment of a genetic variant relies on the clinical context and knowledge of the underlying biology. We outline four scenarios encountered in genetic testing where careful consideration of the origin of genetic variation is required for variant interpretation.
Advances in DNA sequencing
Widespread availability of techniques for deep sequencing of the human genome has accelerated the rate at which the genetic basis of inherited and somatic conditions is revealed. With massively parallel next-generation sequencing, it is possible to accurately detect mutations in small subsets of cells that were undetectable using Sanger sequencing methods. In addition to mutations associated with cancer, low-frequency somatic mutations associated with local tissue proliferations and vascular malformations typical of mosaic overgrowth syndromes have recently been discovered. Extensive genomic analyses of a large number of patients with varying phenotypes have exposed a complex relationship between pathogenic variants identified in the context of inherited and acquired conditions.
Relationship between genotype and phenotype in inherited and sporadic diseases
Deeper understanding of genotype–phenotype relationships in inherited and somatic disease is enabling innovative clinical diagnostics for precision medicine, but we must understand the range of biological possibilities that may explain the genetic data. For example, classic assumptions about inherited variants associated with cancer predisposition have recently been challenged; these assumptions include the need for multiple affected generations, mutations in specific genes being related to a specific spectrum of cancers, or that variants detected in peripheral blood reflect only the germline. Cancers with a strong gender-specific incidence may be passed through the opposite-sex parental lineage, giving the false impression that there is not a heritable syndrome present. It has also become clear that the genotype–phenotype relationship with disease is broader than previously appreciated  and that variants detected in blood may be of somatic origin.
Germline origin for pathogenic variants identified in tumor-based testing
In the course of tumor-based testing, germline cancer predisposition mutations are more frequently identified than in the general population because many cancers have a heritable component. Furthermore, these mutations may not be anticipated because of a lack of a strong family history of cancer, sex-specific incidence of certain neoplasms, or incomplete penetrance or hypomorphic mutations.
Genomic interrogation of cancers has been undertaken in various forms for decades, but the advent of quantitative, single-nucleotide-resolution data of genetic aberrations in cancer has been revolutionary. Recent data reveal that pathogenic genetic variants identified within cancer tissues are of germline origin in about 10 % of both childhood and adult cancers unselected for family cancer history [5, 6]. In these studies, loss of heterozygosity or additional somatic mutations suggest that germline mutations were significantly related to the development of cancer. These findings highlight that one must consider the possibility of a germline origin for pathogenic variants when evaluating cancer tissue, even in the absence of a family history.
Variation in genetic mechanisms for a tumor phenotype
Cancer tissue can provide useful information regarding the origin of a