How family history guides the interpretation of your DNA

In most medical consultations, whether routine or specialized, there is one almost universal question: “Is there a family history of cancer, cardiovascular disease, or diabetes in your family?” Most of us mentally review what we know about our parents or grandparents to answer this question. However, do we really understand the importance of family history in diagnosis?

Collecting family history is key information for almost any type of test, especially genetic testing. Whole exome and genome sequencing provides a lot of information in the form of raw data. In this context, family history acts as an indispensable map to guide the exploration of this genetic information. Without this map, a genetic test can be more complex to interpret or direct toward what we are looking for.

In this article, we will explain why family history has an impact on diagnostic performance when requesting a genetic test and how its correct preparation and interpretation allows the result to be contextualized appropriately.

What is a “Family History” in genetics?

Family history, commonly known as family background, is a detailed record of diseases and health conditions in biological relatives. This information, together with the patient’s personal history, is key to genetic counseling. The information obtained is organized visually in a family tree to facilitate the analysis of inheritance patterns that may indicate an increased risk of developing certain diseases.

Compiling a family medical history is a research process that must cover at least three generations to be truly informative. For each family member, it is crucial to obtain specific information that goes beyond a general diagnosis. Key questions include:

• Basic data: patient identification data and basic information about family members, such as gender, age, etc.
• Ethnicity: ethnic or racial origins of the family, as certain ethnic groups are at greater risk of certain diseases.
• Diagnosed diseases: description of diagnosed medical conditions and age of onset.
• Cause of death in the case of deceased family members.
• Reproductive health: Details of the outcome of pregnancies in women in the family and any complications should be provided.

The 4 pillars of the importance of family history

The meticulous collection of this information has direct and profound implications for the diagnostic process. Its value is based on four fundamental pillars:

1. Guides the diagnostic strategy and the choice of the correct test

The portfolio of genetic tests is extensive, ranging from the analysis of a single mutation to whole genome sequencing. Family history allows for the selection of genes to be analyzed and even the technique required for the study. Sometimes, family history suggests a clear suspicion of disease, and other times the patient presents what is called a “complex phenotype,” which affects different body systems and requires more extensive testing. Requesting the appropriate test increases the chances of finding a diagnosis, optimizing time and resources.

2. Provides crucial context for interpreting genetic results

When interpreting genetic variants, it is common to encounter Variants of Uncertain Significance (VUS). A VUS is an alteration in the sequence of a gene whose clinical impact cannot be determined with current scientific evidence.

In patients with a personal or family history related to a particular disease, the VUS may be the starting point for a family segregation study. This analysis investigates whether the variant is consistently transmitted along with the disease through generations in a family. The observation that a VUS co-segregates with the phenotype (i.e., it appears in affected relatives and is absent in unaffected relatives) constitutes strong evidence in favor of its pathogenicity.

For this reason, family history becomes a fundamental tool for conducting family segregation studies, which are key to helping determine whether the variant found may imply a risk of disease.

3. Reveals inheritance patterns

Analysis of family history can often reveal the pattern of inheritance of a disease across generations. This guides specialists on the molecular basis of the pathology, allowing them to determine whether it follows a dominant, recessive, or X-linked inheritance pattern. In our article, “Diseases and types of genetic inheritance”[1], we explain the characteristics of each of these inheritance patterns in greater detail.

Identifying the inheritance pattern allows us to narrow down the list of candidate genes to study and thus more accurately establish the risk of recurrence for other family members.

It may be diagnostic on its own

In clinical practice, we sometimes encounter families with such a strong history of disease that it suggests a hereditary syndrome, yet no genetic variants related to the disease are detected. It is crucial to understand that this does not rule out a genetic cause, as it may be due to two main reasons: either the causal variant is located in a gene not yet associated with the disease, or it is located in a genomic region not included in the test performed.

Genetic counseling consultation with a specialist

The genetic counseling consultation is a key factor that allows the clinician to gather essential information to determine the most appropriate genetic test based on the clinical suspicion derived from the patient’s personal and family history.

The post-test consultation with the genetic counselor allows for the correct interpretation of the genetic test in the context of the patient’s personal and family history, as well as the possible implications for their descendants or relatives. In addition, based on all the available information, the specialist implements additional tests, specialized medical consultations, or surveillance and prevention measures, even without molecular confirmation.

At Veritas Genetics, we understand that each genetic result must be interpreted within a clinical and family context. Therefore, genetic counseling and the integration of family history are essential pillars of our diagnostic process, ensuring that your DNA information is translated into actionable and relevant knowledge for you and your family. If you would like more information, please do not hesitate to contact us.