Q: One of my patients is interested in getting genetic testing done, but the father is unavailable. Is genetic testing still possible and useful?
A: The answer to your question revolves around what is the added advantage of “triome” over “singleton” sequencing.
Singleton: This term refers herein to when only DNA from the patient is sequenced. While not perfect, most of the advantages of sequencing can be gained from testing the patient alone, at least in many patients (see below).
Triome: This term refers to when DNA from the patient and both parents are sequenced. Triome sequencing offers certain advantages over singleton sequencing:
The primary advantage of triome is the identification of de novo variants, which are “new mutations” that are present in the patient but absent in both parents. Triome sequencing is frequently often used in patients with neurodevelopmental disorders (intellectual disability, autism, etc.), epilepsy, “syndromes”, and/or birth defects, whereas de novo variants are fairly common and oftentimes the main cause of the patient’s disease.
Most metabolic disorders are autosomal recessive, in which both parents are (usually unaffected) carriers of one disease-causing variant each, and the patient inherited both of these variants, resulting in disease. In these situations, either the patient is heterozygous for two different variants (a compound heterozygote), or homozygous for the same variant inherited from both patents. When two variants are identified, to be disease causing they should be on different chromosomes, inherited one each from both parents (“in trans”). The alternative, both variants on the same chromosomes, inherited from only one parent (“in cis”), is likely not disease causal (but could be a risk factor). The easiest, and often the only, way to determine the “phase” of the variants (in cis versus in trans) is to sequence at least one parent.
In the case that one parent is clinically affected, sequencing can determine which of several “variants of uncertain significance” were inherited from the affected parent. Obviously, these variants would be more important than variants inherited from the unaffected parent.
The purpose of triome sequencing is to better understand the sequence results in the patient. Triome sequencing is NOT intended to identify genetic disease or risks is the parents, most of which will not be identified. Of course, triome sequencing will identify a parent as having a disease-causing variant if both the patient and a parent share the variant.
Of note, triome sequencing can be used for large panels, whole exome sequencing (WES), and whole genome sequencing (WGS).
As a practical matter, triome sequencing is recommended for patients with neurodevelopmental disorders (intellectual disability, autism, etc.), epilepsy, “syndromes”, and/or birth defects, whereas in many other settings, singleton sequencing is appropriate.