According to the National Organization for Rare Disorders (2021), Pulmonary Hypertension (PH) is a form of high blood pressure that affects the arteries in the lungs and the right side of the heart, which is caused by narrowed, blocked, or damaged blood vessels in the lungs; thus, the flow of blood through the lungs is hampered, requiring the right side of the heart to work more extensively to pump blood. Unfortunately, as mentioned by the same source, this can eventually lead to the weakening and enlargement of the heart, or even heart failure. The Pulmonary Hypertension Association (n.d.) reveals that depending on the underlying cause of the condition, several types of PH were identified: Group 1: Pulmonary Arterial Hypertension (PAH), Group 2: Pulmonary Hypertension Due to Left Heart Disease, Group 3: Pulmonary Hypertension Due to Lung Disease, Group 4: Pulmonary Hypertension Due to Chronic Blood Clots in the Lungs, and Group 5: Pulmonary Hypertension Due to Unknown Causes. In particular, Group 2: Pulmonary Hypertension Due to Left Heart Disease, also known as Pulmonary Hypertension Type 2 (PPH2), is the type of PH that runs in the paternal side of my family. The National Organization for Rare Disorders (2021), American Heart Association (2018), and Mayo Clinic (2020) reveal that Familial Pulmonary Hypertension Type 2 (PPH2) is a chronic genetic disease characterized by shortness of breath during exercise or at rest, fatigue or weakness, dizziness or fainting spells, swelling in the legs or ankles, chest pain and discomfort, enlargement of the right ventricle of the heart, bluish lips or skin, rapid or irregular heartbeat, coughing up blood, and decreased exercise tolerance. These are caused by the thickening and stiffening of the arteries in the lungs, causing problems with how the heart squeezes or relaxes, or problems with the valves on the left side of the heart. As a result, the heart may not be able to keep up with the blood that returns from the lungs, which causes a “backup” of blood that can raise the pressure in the lungs.  As explained by OMIM (n.d.), it is caused by a variety of mutations in the SMAD9 gene on chromosome 13q13. For instance, the same source indicates that researchers have identified heterozygous truncating and heterozygous missense mutations in the SMAD9 gene among PPH2 patients that were examined in their respective studies. Moreover, although it is inherited in an Autosomal Dominant Genetic Inheritance Pattern as OMIM (n.d.) suggests, it manifests Incomplete Penetrance which means that even if individuals have mutations in SMAD9, there is a chance that they do not show symptoms for the disease. Furthermore, Mayo Clinic (2021) reveals that pulmonary hypertension can also have a Variable Age Of Onset, with affected individuals often displaying symptoms from ages thirty to sixty and with an increasing risk for having the disease as a person grows older (National Heart, Lung, and Blood Institute, n.d.). Based on the information provided above, analyzing the family pedigree chart and determining which individuals have a particular genotype can be quite trickly because the disease manifests incomplete penetrance and a variable age of onset. In other words, there might be individuals in the pedigree chart who are heterozygous for the disease but will never manifest symptoms and those that will manifest symptoms of the disease later on but are not yet showing symptoms as of now. To begin with, it is first important to understand that PPH2 has an autosomal dominant inheritance pattern, which means that, by Mendelian genetics, homozygous dominant (HH) and heterozygous (Hh) individuals are supposed to be affected by the disease and those who are homozygous recessive for the disease (hh) have a normal phenotype and will not suffer from its symptoms. Looking at the family pedigree chart, there are only three individuals that were/are affected: I1, II3, and II5 (our paternal grandpa, uncle, and aunt). However, on the other side of the pedigree chart, my mother’s side of the family, no one is affected by the disease. Upon confirming through the elders (cousins of my maternal grandparents) that there is no history of PPH2 among the members of the Ruiz, Serios, Iwayan, and Canque families that were closely related to my grandparents (I3 and I4), I have speculated that my grandparents were homozygous recessive, which means that they were not affected and they were not in risk for the disease when they were alive. This assumption aligns with the current data that I have of their children and grandchildren. My mother and all of her siblings currently do not suffer from any symptom of the disease (II7, II8, II10, and II12) and so do their children (III6 to III14). This led me to believe that just like their parents, they might also be homozygous recessive; however, this same conclusion cannot be applied to me and my sister (III6 and III7). After all, some members of the paternal side of our family have/had PPH2. To confirm the assumption that the members of the third generation of the maternal side of my family (aside from me and my sister) have homozygous recessive genotypes, I asked my aunt and uncle-in-laws if they have a history with PPH2 in their families. All of them replied that they do not have / did not have family members who suffer / suffered from the disease. This implies that indeed, all of the members of the third generation of the maternal side of our family may really have homozygous recessive genotypes. Moreover, to determine the genotype of IV3, I asked III10, our cousin-in-law (IV3’s mother), if she had a family member from the last three generations of her family who had PPH2. She replied that she did not know of any member who has/had the disease. This is why I assigned her the homozygous recessive genotype as well, which means that IV3 has a homozygous recessive genotype and is not, in any way, at risk of acquiring PPH2. To recap, my maternal grandparents both have homozygous recessive genotypes, which means that their children will have 100% chance of having homozygous recessive genotypes as well. Upon the confirmation that my aunt- and uncle-in-laws have homozygous recessive genotypes, I assumed that their children will have 100% chance of having homozygous recessive genotypes as well. And finally, after contacting my cousin-in-law and determining that she has a homozygous recessive genotype, I concluded that she and my cousin will have a child with a homozygous recessive genotype because they both have homozygous recessive genotypes. On the other hand, as I have mentioned earlier, three family members that belong to my paternal side of the family have/had the disease. I have also mentioned that determining their genotypes may be challenging because of the disease’s incomplete penetrance and the variable age of onset among those who are affected. However, in cracking puzzles like ones provided by pedigree analysis, one must start assessing the genotypes of the ones in the oldest generation. Since my grandfather (I1) had PPH2, I assumed that he either had an HH or Hh phenotype. Currently, I have no means of identifying whether he had an HH or an Hh genotype because my family does not have any data about my grandfather’s parents, especially regarding whether both, just one, or none of them were affected by the disease. (My grandfather survived the Japanese occupation in the Philippines and he was the only survivor in his family. He was captured and tortured by Japanese soldiers but he eventually escaped. He travelled on foot to Victorias City from Murcia and he was only able to bring with him photos of his mother and brother.). Moreover, to determine the genotype of my paternal grandmother (I2), I asked my grandma’s niece if she knew any of my grandmother’s relatives who had the disease and she said that she does not know of anyone in their family who had it; therefore, I assumed that my paternal grandmother has a homozygous recessive phenotype. This means that if I1 has a homozygous dominant genotype, then there is a 100% chance that I1 and I2’s child will have a heterozygous genotype and may be affected by the disease; however, if he has a heterozygous genotype, then it is expected that 50% of their children will have the heterozygous genotype and the other 50% will have the homozygous genotype. Both the results of the possible crosses of my paternal grandparents  are in concordance with the observed conditions of their children, granting that two of whom (II3 and II5) have PPH2 while the other two do not show symptoms for it. Very simply, one can say that the I1 and I2 may have had heterozygous and homozygous recessive genotypes, respectively because their children are 50% affected and 50% normal; however, PPH2 does not work directly in that way. Remember that it has incomplete penetrance and a variable age of onset among the affected, which means that heterozygote individuals may not suffer from the disease or s/he may suffer from the disease later in life. Therefore, basing on the results of the crosses between I1 and I2 and the fact that PPH2 manifests incomplete penetrance and variable age of onset among the affected, I can say that the affected children, II3 and II5, have heterozygous genotypes while those who currently do not show any type of symptom are either heterozygous or homozygous recessive individuals.    To begin addressing the concerns raised by my sister, I am going to first identify the genotype of one of our nieces, IV1. For the paternal side of the family, I have also asked my aunt- and cousin-in-laws (II2, II4, III3, and III5) if their families had a history with PPH2 to which they answered that they did/do not have any family member in the past or right now who have the said disease. Therefore, I assigned the homozygous recessive phenotype to all of them. Thus, IV1’s grandfather, II1, who is either heterozygous or homozygous dominant, is crossed to II2, who has a homozygous recessive genotype. Thus, their children (III1 and III2) must also have either homozygous recessive or heterozygous genotypes. Since IV1’s mother is III2 and her father is III3, who has a homozygous recessive genotype, then sadly, she may have a heterozygous genotype, which means that she may have PPH2. Fortunately, she still has a chance of having a homozygous recessive genotype, thanks to her homozygous recessive father and a recessive allele from her mother. Secondly, our other niece, IV2, has a grandfather, II3, who has a heterozygous genotype and a grandmother, II4, who has a homozygous recessive genotype, then her father, III4, can either have a homozygous recessive or heterozygous genotype. When crossed with her mother, III5, who has a homozygous recessive genotype, then the child that they will have can either have a homozygous recessive or heterozygous genotype.  This means that IV2 is also at risk of having PPH2 but there is still a chance that she will not have the disease. Finally, my sister’s concern whether we (III6 and III7) are at risk of having PPH2 as well can be addressed by looking at our father’s genotype. Based on the analysis of our paternal grandparents’ possible genotypes, it was revealed that our father (II6) may either have a homozygous recessive or heterozygous genotype, which means that paired with our mother (II7) who has a homozygous recessive genotype, we are still at risk of having PPH2 because we can either have a homozygous recessive or heterozygous genotype. Although this information may make my sister feel that we are unfortunate, I would tell her that luckily, there might be a chance that, even if we are indeed heterozygotes, we will not be affected by the disease because of its incomplete penetrance. Moreover, as revealed by Ghofrani et al. (2017); Rabinovitch (2012), and Thakur et al. (2020), while genetic factors may largely contribute to the development of PPH2, it is not solely caused by gene mutations. To explain, the same authors stated that several studies reveal that various environmental factors such as, but not limited to, exposure to smoking, high altitude, occupational dust, and air pollution can increase one’s likelihood of developing PH2, especially those who may have a predisposition to the disease based on his/her genes. In addition, Simonneau et al. (2019) reveal that comorbidities like sleep apnea, pulmonary embolism, and obesity may also contribute to disease development and progression. For instance, in a study by Thakur et al. (2020) that investigated the association between environmental factors and PPH2 in India, it was revealed that high exposure to indoor and outdoor air pollution is significantly associated with an increased risk of having the disease. This is also supported by Rabinovitch (2012) who concluded that although genetic susceptibility plays a large role in disease pathogenesis, it is not the sole cause of PPH2. In other words, while genetic factors may contribute to the development of PPH2, it is a complex disease influenced by various environmental and lifestyle factors as well. Therefore, I would tell my sister that since there might be a chance that we will have the disease (as revealed through the pedigree analysis), then it would be better to make sure that we take good care of ourselves and live a healthy lifestyle so as to, as much as possible, decrease our chances of having the disease. The same advice can be given to our cousin and cousin-in-laws so that as soon as possible, they can start raising our nieces through methods that will ensure that they will grow as healthy as possible.