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Assess distribution of congenital phenotypes #68
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What proportion of HPO phenotypes are congenital?gpt_check <- HPOExplorer::gpt_annot_check()
table(gpt_annot$annot$congenital_onset) There's a fairly even distribution across response categories. What proportion of our phenotype-cell associations would be left if we filtered on congenital phenotypes?results <- MSTExplorer::load_example_results()
results <- results[q<0.05]
results <- HPOExplorer::add_gpt_annotations(results)
table(results$congenital_onset, useNA = "always")/nrow(results)*100
Which branches of the HPO are most enriched for congenital phenotypes? (figure for GPT HPO paper)Ordered by percentage of phenotypes that are always congenital. Note that "abnormality of prenatal development or birth" is no.1. Neoplasms and immune disorders are further down. Will add this to the GPT paper. All HPO termsOnly HPO terms under "Phenotypic abnormality" |
Which branches of the HPO are most enriched for phenotypes with fetal cell type associations? (figure for Rare Diseases paper)Abnormality of limbs has is the most enriched for fetal celltypes. results <- MSTExplorer::load_example_results()
plot_congenital_annotations_out <- MSTExplorer::plot_congenital_annotations(
by_branch=TRUE, ## New arg implemented
results = results) |
What proportion of phenotypes and/or diseases with existing gene therapies are congenital (eg. SMA, sickle-cell anaemia, haemophilia, thalassemia, Leber congenital amaurosis)?Ultimately, what we're really asking is whether gene therapy (or any kind of therapy) will be effective for treating a phenotype once the phenotype has already manifested. There are several implicit assumptions here:
1. Treatments cannot be applied prenatallyThis has historically been true but there are now techniques being more commonly used in hospitals such as prenatal surgery. There have also been recent successes with the prenatal treatment of genetic disorders like Pompe disease using enzyme replacement therapy.
So while it's still early days for prenatal treatment with biologics, I expect we'll be seeing more of this in the near future. 2. Treatments are ineffective once phenotypes have manifestedSee below for some cases where this is (currently) true and several where it is not true. Cases where therapy post-manifestation is ineffectiveSMA@NathanSkene and I discussed this and concluded that there is a distinction to be made between diseases being congenital and phenotypes being congenital. In fact, just today I listened to a podcast where Wendy Chung mentioned that phenotypes of SMA often don't appear until 6mo after birth, at which point it can be too late as the child will likely die by 12mo of age. Physical malformationsMany physical malformations due to developmental disorders are not currently treatable with gene therapy. Here, surgery + other medications may be more effective (eg cleft palate, hydrocephalus). For others, no currently available treatments can help beyond treating secondary symptoms like seizures (eg agenesis of the corpus collosum). Gene therapy could still be helpful for these patients for preventing the physical malformation from re-emerging, such as in my example of skeletal dysplasia where initial surgery on the rib cage could allow the child to breath while follow up with gene therapy might allow the chondrocytes to grow normally and thus not cause constriction of the organs as the child continues to grow. Cases where therapy post-manifestation is effectiveBlood disorders: SCA, thalassaemiaOn the other hand, diseases like Sickle Cell Anemia are congenital. Some phenotypes of SCA are also congenital, such as 'Sickled erythrocytes', while others appear several months after birth. Same goes for thalassaemia. Despite the fact that some of the core phenotypes are congenital in these diseases, these are some of the most successful gene therapies to date. DMDDuchenne Muscular Dystrophy (DMD) first begins to manifest as phenotypes around 3-4 years of age. Existing gene therapies don't restore function that's already been lost at the time treatment begins, but it can slow (and possibly stop) the progression of the primary phenotypes such as muscle weakness. As with many diseases, earlier detection and diagnosis is better but gene therapy still can have profound effects even post-phenotype manifestation. Conclusions
So basically, whether a phenotype can be treated post-manifestation (whether it's congenital or non-congenital) really depends on the particular phenotype. After excluding physical malformations, I don't see any strong evidence that congenital vs. non-congenital is a good predictor of treatability by gene therapy. It all depends on 1) the rate of progression (eg DMD is relatively slow, SMA is fast), 2) whether the particular phenotype causes permanent tissue damage. |
It's also worth mentioning, that there's non-congenital phenotypes that aren't treatable by gene therapy post-manifestation.
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There are some scenarios where non-congenital phenotypes are more amenable to [gene] therapy than congenital phenotypes:
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I’m leaning towards that your idea of filtering by malformations, rather than congenital onset might be the right one. Above results sound great from a skim read, looking forward to discussing.
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There are some scenarios where non-congenital phenotypes are more amenable to [gene] therapy than congenital phenotypes:
* prenatal therapy is not available
* the risk for the phenotype can be accurately predicted before its manifestation. you can do this with genetics in cases where the parents happened to do genetic screening, and the genetic variant is highly penetrant (not always the case even with rare mutations). however, in most cases genetic screening only occurs after the child starts manifesting phenotypes. so non-congenital doesn't necessarily mean opportunity for early detection.
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@KittyMurphy
@NathanSkene and I discussed whether congenital phenotypes should be excluded from the gene therapy target prioritisation pipeline.
@NathanSkene suggested that congenital phenotypes should be removed because they are mostly associated with morphological/gross anatomical abnormalities which would not be amenable to gene therapy.
I agree that morphological phenotypes wouldn't be good candidates for gene therapy, but I think removing all congenital phenotypes isn't the best way to filter out these scenarios. Especially when we have "physical_malformations" as a GPT annotation we can use to filter on directly.
Some thing we need to check:
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