he correct answer is C, variable expressivity.
Gorlin-Goltz syndrome, also called nevoid basal cell carcinoma syndrome, is most frequently due to a mutation in the PTCH1 gene. PTCH1 is a tumor suppressor gene located on chromosome 9 that is part of the hedgehog signaling pathway. Most patients (≥ 90%) develop multiple basal cell carcinomas of the skin. Other signs and symptoms can include keratocystic odontogenic tumors, cardiac fibromas, ovarian fibromas, bone and skeletal abnormalities, and intracranial calcifications (Epstein et al., Nat RevCancer 2008). This rare genetic disorder is transmitted in an autosomal dominant (AD) manner with complete penetrance and variable expressivity.
Variable expressivity (or variable expression) in genetics is when there is a range of signs and symptoms that can occur in different individuals with the same genetic condition. In other words, it is when some individuals with the disorder have mild symptoms, but others have severe or life-threatening manifestations of the disorder. The variation can be interfamilial (between different families who carry the mutation) or intrafamilial (within a family, with different family members presenting with different severity of symptoms). Darier disease, Marfan sydnrome, and type I neurofibromatosis are disorders that have a high to complete penetrance in adulthood but a wide range of severity due to variable expression.
Variable expressivity is likely due to a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. This is also the case for reduced or incomplete penetrance, where some individuals with a mutation do not have any manifestations of the disorder at all.
Loss of heterozygosity (LOH) is a chromosomal event that results in loss of the entire gene and the surrounding chromosomal region on one chromosome. This leaves only one chromosome in the individual cell with that gene present. LOH is an important occurrence in cancer development. Patients who have a mutation in a tumor suppressor gene (TSG) on one chromosome and a normal functioning gene on the other chromosome in the pair will not develop malignancy. However, if there is loss of that gene during cell division, this location now has a LOH and no properly functioning TSG to prevent the development of cancer.
Mosaicism is when an individual has two or more sets of cells that differ genetically from one another. It can be caused by an error in cell division very early in the development of the fetus. Many genetic skin disorders demonstrate cutaneous mosaicism, including Proteus syndrome, where an abnormal AKT1 gene in some cells produce a growth activating protein resulting in various forms of overgrowth and nevi throughout life. (Milani and Chauhan., StatPearls 2020).
X-inactivation refers to the fact that most of the cells in females will only have 1 active X chromosome, despite having two X chromosomes present. Genetically, females will have 2 X chromosomes, whereas males will have an X chromosome and a Y chromosome. In a highly coordinated process, females transcriptionally silence one of the two X chromosomes. The process is random, and each cell will have an ~50% chance of having the mother's X chromosome or father's X chromosome silenced. However, there can be skewed X-inactivation that manifests disease in females who are heterozygous for X-linked gene mutations. Incontinentia pigmenti is an example of a skin disorder caused by defect in X-inactivation that produces a whorled dyspigmentation pattern that follows Blaschko's lines (visual appearance of the pattern of lines described by the dermatologist Alfred Blaschko). (Sun and Tsao. Journal of Investigative Dermatology 2008)
Clinical Pearl: In genetics, variable expressivity is when there is a range of signs and symptoms that can occur in different individuals with the same genetic condition. In other words, it is when some individuals with the disorder have mild symptoms, but others have severe or life-threatening manifestations of the disorder.
It is important to understand important genetic factors that can affect clinical disorders and their presentation for the BASIC Exam. This includes loss of heterozygosity, incomplete penetrance, mosaicism, and variable expressivity.
Other References:
(Taeubner et al. Trends Cancer 2018)
(Zlotogora. Genet Med 2003)
