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The interplay between genes and their environment was also a listed factor for modified penetrance. In relation to PD, an independent research team found caffeine consumption and cigarette smoking could decrease the risk for PD (dose-dependently) (Hernan et al. 2002). In addition, epidemiological studies have shown exposure to pesticides is an adverse risk factor for PD (Richardson et al. 2009).
The biggest risk factor for PD is aging due to the relationship of the mutations increased by aging and penetrance. As age increases, mitochondrial function declines, causing more mutations in the mitochondrial DNA (mtDNA). Specific mutations in the mtDNA were detected in patients with PD. In addition, the association of mtDNA haplogroups with specific mtDNA variants has been linked to PD. A reduced risk was found for a variant including ND3 in a section of the mitochondrial respiratory chain, but an increased risk of PD was found for patients with an alternative superhaplogroup in the mtDNA (Zanon et al. 2018). Therefore, mutations, such as the mtDNA deletions, and aging are related to the penetrance of PD because of the allowed nuclear mutations that act on mitochondrial mechanisms.
This study also presents the argument that protein interactions can influence penetrance. Both Parkin and PINK1 proteins are crucial in many factors regulating mitochondrial activity (Zanon et al. 2018). The interactions between the PD-causing proteins and what they bind to may influence disease penetrance as mitochondrial function and quality control might fail during aging or from mutations in genes that code proteins involved in the mitochondrial functioning pathways. The effects from the issues caused in the mitochondrial process are deleterious which will lead to degenerating human neurons causing PD.
Due to the high rate of reduced penetrance in PD, distinguishing the factors that lead to incomplete or delayed onset could be able to protect humans from developing the disease or delay the onset. The environmental modifiers, gene modifiers, mtDNA alterations, and protein interactions are all possible factors for nonpenetrant or highly reduced penetrant forms of PD. These are all involved in sustaining successful mitochondrial function and their confirmation of influence could help stop disease progression (Zanon et al. 2018). While this study didn’t continue to offer solutions to find the answers they are now looking for regarding the expected variables for the reduction in penetrance, it successfully identifies possible options regarding modified penetrance that is necessary to understand in the context of inherited disease.

Figure 5: “Modifying factors possibly underlying nonpenetrant or highly reduced penetrant forms of PD” (Zanon et al. 2018).
Allele Number and Mutations- HSRC
In most autosomal dominant-based diseases, the effect of the disease is usually significantly higher in homozygotes (Shawky 2014). In a study completed by Basel-Vanagaite et al. (2006), Hirschsprung disease was studied to allele penetrance of RET proto-oncogene gene mutations. These mutations are a low-penetrance mutation which creates a loss-of-function mutations with incomplete penetrance and variable expressivity. “Although the heterozygous IVS + 5G – > A mutation is of low penetrance for short segment HSCR, the homozygous state is fully penetrant for total agangliosis (where nerves missing from the intestine cause stool passing issues) or long segment HSCR” (Basel-Vanagaite et al. 2006). For these reasons, the penetrance of the RET gene mutations is dependent on the allele dosage and modifier.
The different variations of HSCR are short-segment disease (s-HSCR) where aganglionosis is restricted to the rectosigmoid colon which occurs in 80% of individuals (Basel-Vanagaite et al. 2006). There is also long-segment disease (L-HSCR) where aganglionosis extends proximally to the sigmoid colon which occurs in approximately 15% of individuals. Third, there is total colonic aganglionosis (TCA) that affects the entire large intestine and is usually fatal which occurs in approximately 5% of individuals. Last, there is total intestinal aganglionosis (TIA) that affects the area extending from the duodenum to the rectum which is the rarest and is usually fatal (Basel-Vanagaite et al. 2006).
The study looked at one Israeli-Arab family (because the disease most prevalent in Caucasian populations). The pedigree chart shows one branch with three sisters with TCA and one female with L-HSCR. In the second branch of the family, there is one male with S-HSCR (Basel-Vanagaite et al. 2006).

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Figure 6: Pedigree chart for the Israeli-Arab family patients (Basel-Vanagaite et al. 2006)
The researchers used a linkage analysis to the RET gene locus using polymorphic genetic markers followed by sequencing the SNP rs2435357. Then screening for mutations of the coding sequence of the RET gene was completed (Basel-Vanagaite et al. 2006).
The study found that the mutation “IVS6+5G?>A” is of full penetrance (100%) in the homozygous state but of low penetrance in the heterozygous state (less than 12.5% when including untyped carriers in generation 1). In addition to this, the homozygous patients present a minimal variation of expression because only TCA with small bowel movement and L-HSCR were found (Basel-Vanagaite et al. 2006).
All the family members from this study who were homozygous for the RET gene mutation have severe forms of HSCR. However, none of the family members in this study carries the hypomorphic (partial loss of gene function) allele rs2435357 which was shown in previous studies as a highlighted enhancer role for this region. There were two males (II-1 and III-2) who were heterozygous for the splice mutation on hypomorphic allele but III-2 is affected with S-HSCR while the father with an identical haplotype (II-1) was unaffected. While it is clear that the nature of the mutation and the allele number influence penetrance, the researchers believe there are additional genetic changes at play for the variable expressivity of the disease in this study (Basel-Vanagaite et al. 2006).


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