Pedigree Analysis and Risk Assessment

The genetic family history, or pedigree, is a valuable tool for assessment of disease risk. Use of standardized symbols and nomenclature in pedigrees is recommended to ensure accurate communication of information to end users. There are common questions which should always be asked during collection of a family health history; however, questioning is often tailored for the condition under evaluation. Pedigrees may also help assess disease transmission patterns in the family which may be Mendelian (autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, Y-linked), chromosomal, mitochondrial, or multifactorial. When atypical patterns of inheritance are seen, consideration should be given to other factors which can influence transmission including, imprinting, uniparental disomy, unstable DNA, gene-environment interactions, mosaicism, and synergistic heterozygosity. Recognition of the mode of inheritance within a family can be useful for estimating disease risk for family members or offspring. Risk assessment also may be confounded by logistical factors, such as family dynamics and limited information, or processes such as variable expression of disease, penetrance, heterogeneity, mosaicism, lyonization, or consanguinity. Many different laboratory methods are used for direct detection of genetic mutations associated with disease. When direct mutation analysis is not feasible, gene discovery or assessing risk for disease may be facilitated by linkage analysis or genome/exome sequencing. Bayesian analysis is a statistical construct that allows for the combination of incremental contributors to risk to determine an individual’s risk of developing or transmitting a disorder.