HOW ARE GENES RESPONSIBLE FOR GENETIC DISORDERS IDENTIFIED?
In general, the ease with which the genetic basis of a disorder may be determined is related to the prevalence of the disease-causing variant(s) in the population at large, to whether there is a family history of the disorder and DNA from other family members is available for analysis, and to the mode of inheritance (e.g., Mendelian, polygenic, and/or high vs. low penetrance).
For example, the cause of certain forms of hearing loss in infants is often relatively easy to determine. This is because hearing loss is relatively common in newborns (one out of every 500 children is born with hearing loss) and is, therefore, well-studied. It is known that two-thirds of hearing loss cases in newborns have a genetic basis. Most newborns with hearing loss (70%) have no other symptoms. When hearing loss is the only genetic disorder present (i.e., there are no other symptoms), and family history suggests the disorder is being inherited in a Mendelian recessive fashion, it is commonly due to variants in one of two genes, GJB2 or GJB6.
In other cases, a much larger but reasonable set of candidate genes can be analyzed. For example, regarding congenital newborn hearing loss that does not have the characteristics associated with GJB2 or GJB6 mutations, a set of up to about 100 genes may be examined for variants associated with hearing loss. Through the use of probes that target these genes, the relevant regions can be selected from patients and analyzed. This has proven to be successful in many cases. Understanding the genetic basis of hearing loss may be helpful in determining how to manage the disorder in an affected child. Also, the information may help family members make informed medical and personal decisions.
Targeted approaches that screen a defined set of candidate genes for potentially deleterious variants do not reliably find the causative mutations for many diseases. For example, in inherited hypertrophic cardiomyopathy (HCM), a common cause of sudden cardiac arrest in young athletes, family members may have a strong interest in being tested to determine whether they also carry the mutation underlying this silent, devastating disease. Therefore, identification of the disease-causing mutation is important. However, the disease-causing variant can be detected in only up to 60%–70% of inherited HCM cases using targeted approaches.
Exome or whole genome sequencing often is attempted when more targeted approaches fail. Ideally, the DNA sequences for the entire family including the father, mother, and siblings are determined. Based upon the pattern of inheritance of a disease within a family, the likely genetic basis of the disease (e.g., recessive vs. dominant, familial vs. spontaneous) is deduced. This information is integrated with the results from exome or whole genome sequencing to identify genes and gene variants that might be causing the disease. The signs and symptoms that characterize a disease provide some insight into the likely underlying dysfunctional biological process(es); in some cases, available basic research on a disease also helps further characterize the underlying biology. This insight into the biology of the disease can be helpful in narrowing down which of the many genes and their variants identified by the sequencing are actually causing the disease.