Isabella's TRIP12 Gene Deletion - 50k goal
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This week is going to be one of most important first steps to bringing awareness to Isabella's diagnosis of her RARE Gene deletion of the Trip12 Gene. I'll am going live with a film discussing her diagnosis, The Trip12 Gene, her current & future needs, and our plan to find a cure.
We will find a cure and we need your help!
Isabella is one of very few people (20) in the world to have a rare deletion of her Trip12 Gene.
Please Join us during this LIVE event & Film release to highlight Isabella’s life, diagnosis, share insights on her condition, to raise funds for her immediate medical needs.
This is the amount needed over the next 3 years to help Isabella with some of her most crucial needs, Service dog that can detect & alert us of potential seizures, Custom mouth guard to help with her airway, behavior & speech therapy, and a custom tablet to help her communicate with us.
---> Order TRIP12 Merch and all Profits go to the overall fundraising goal!
https://farrellsteven.wixsite.com/trip12
--- > Gofundme link:
https://www.gofundme.com/f/isabellas-trip12-gene-deletion-50k-goal
Follow her Story on Facebook:
https://www.facebook.com/trip12genedeletionisabella
More about Isabella:
On Monday Oct 18, 2021, at 8:45am we got on a zoom call with genetic Counselor Rachel Palmquist from Primary Children’s Hospital. The call was scheduled to learn about our recent Exome Clinical Sequence test done on Isabelle, Courtney, and myself to see if she had a genetic mutation, deletion, or nothing at all. Geneticist
Then Rachel shared the terrible heart wrenching news. Isabella is one of 20 to have a rare Genetic Deletion of her Trip12 Gene.
The news hit us like a ton of bricks. I had a basic understanding of genetics to ask a few follows up questions but in no way was I or Courtney equipped to hear the news and to understand it fully.
As I started researching what this meant for Isabella, my anguish for her felt like nothing I’ve ever experienced in my life.
It felt like the floor just fell out from underneath me and I was in a free fall for the next few days and weeks.
Isabella had a rough start to this life. Oct 16 2016, she was delivered via emergency c-section because her umbilical cord was wrapped around her neck. During her time in the Nicu she didn’t have any visible signs of brain damage but struggled to feed and breath without oxygen support.
After 3 weeks in the Nicu, Isabella was cleared to go home and with a clean bill of health.
We had no reason to believe she had any genetic or underlining health conditions outside of being a normal preemie baby.
We were met with some health challenges shortly after her first year.
Isabella suffered from
Global developmental delays, Strabismus (abnormal alignment of the eyes) trichotillomania (excessive & compulsive pulling of her hair) Tremors & ongoing ear infections for years on end.
Tubes helped very little, and she would get at least 1 ear infection per month that would last for 2 weeks, and this went on for years!
We attempted to take on each of these conditions individually, but it was the daily tremors that concerned us the most, aside from her developmental delays which we thought she would quickly grow out of.
We visited a neurologist to discuss her tremors and went through a variety of different tests that were all inconclusive. As a last-ditch effort to find answers we dropped 5k to get a genetic test and what would you know, nothing. It’s not genetic (at least that’s what we thought)
During this same time in her life, we are visiting primary children’s Hospital to find out why she is having severe speech delays and lack cognitive growth. Test after test and tens of thousands of dollars later to only have revealed no new insights.
No answers
All the while Isabella’s health is worsening, and new conditions keep adding to the stack.
Once Covid -19 hit in early 2020, most tests & office visits became a thing of the past and our journey to find answers was halted. As parents we felt defeated and hopeless of ever finding answers, so for now we were focusing on treating the symptoms.
In the Fall of this year 2021 We decided to act on the recommendation of getting a full Exome Clinical Sequence of the 3 of us, A test we were not familiar with.
Apparently, this test is different from your normal Genome test that we did 2 years earlier.
Clinical Whole Exome Sequencing is a test for identifying disease-causing DNA variants within the 1% of the genome which codes for proteins (exons) or flanks the regions which code for proteins (splice junctions)
it’s not the cheapest test to conduct, 22 thousand dollars and not a lot of support from health insurance.
The results from the test revealed, Isabella is one of 20 to have a rare Genetic Deletion of her Trip12 Gene. The physical health conditions & treatments from this rare genetic deletion is the purpose of this Fundraising event. We thank you for helping Isabella and this greater cause to bring awareness to children with rare genetic conditions.
---> Order TRIP12 Merch and all Profits go to the overall fundraising goal!
https://farrellsteven.wixsite.com/trip12
--- > Gofundme link:
https://www.gofundme.com/f/isabellas-trip12-gene-deletion-50k-goal
Follow her Story on Facebook:
https://www.facebook.com/trip12genedeletionisabella
You can now watch the FULL Film about Isabella HERE:
Please follow us on Facebook!
Mutations or deletions in the (TRIP12) gene the long name for it is called the thyroid hormone receptor interactor 12, which encodes an E3 ligase in the ubiquitin pathway, have been associated with Autism spectrum disorder (ASD).
In addition to autistic features, TRIP12 mutation carriers showed moderate to severe intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts.
It is not surprising that many members of the ubiquitin pathway have been associated with diseases including cancer, such as BRCA1-associated breast and ovarian cancer, neurodegenerative diseases, such as Parkinson and Alzheimer disease, neurodevelopmental phenotypes, and autism spectrum disorder (ASD).
More specifically, mutations in HECT (homologous to E6AP C-terminus), type E3 ligases have been shown to be causative for neurodevelopmental disorders, such as UBE3A (ubiquitin-protein ligase E3A, OMIM mutations in Angelman syndrome and HUWE1 (Hect, Uba, and Wwe Domains-Containing 1, OMIM 300697) variants in X-linked intellectual disability (ID)
Hence, mutations in members of the ubiquitin pathway and especially E3 ubiquitin ligases are important contributors to neurodevelopmental pathophysiology
The identification of novel genetic causes of ID and ASD has been subject of intensive research.
First thing we will jump into is something called the ubiquitin pathway.
The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting.
It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders.
Learning more about the TRIP 12 Gene and Exons 37-41 that Isabella has a deletion of and it’s a bit overwhelming.
From the surface Individuals with a Trip12 deletion can have developmental delay, extremely short stature, small hands, dysmorphic facial features, hearing loss, and epilepsy but a lot more is at stake due to the transcription factors and eventually cell degradation.
The predicted 1,992-amino acid TRIP12 protein contains a putative transmembrane domain.
Analysis detected TRIP12 expression in all 16 human tissues examined, with the highest expression in skeletal muscle and testis, lower expression in heart, kidney, spleen, thymus, prostate, ovary, placenta, and White blood cells, and the lowest expression in brain, lung, liver, pancreas, small intestine, and colon.
The thyroid hormone receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. They must specifically interact with a number of proteins as they progress from their initial translation and nuclear translocation to hetero-dime-er-ization with retinoid X receptors (RXRs), functional interactions with other transcription factors and the basic transcriptional apparatus, and eventually, degra-dation
It’s interesting to learn the protein expression of this gene on Exons 37-41. They interact with the following with median read count per base of 3.2-9.9+
Testis
Cells - EBV-transformed lymphocytes
Cells - Cultured fibroblasts
Liver
Kidney - Medulla
Whole Blood
Spleen
Pancreas
Brain - Frontal Cortex (BA9)
Kidney - Cortex
Heart - Left Ventricle
Brain - Spinal cord (cervical c-1)
Brain - Cortex
Brain - Cerebellum
Brain - Cerebellar Hemisphere
Brain - Putamen (basal ganglia)
GENE SUMMARY
The TRIP12 gene is part of the HECT domain, E3 ubiquitin ligase family The TRIP12 protein is expressed in multiple tissues and thought to play an important role in a number of processes including ubiquitin fusion degradation and regulating DNA repair and cell growth
variants in the TRIP12 gene have been observed in individuals with syndromic or non-syndromic intellectual disability; additional features may include autism, speech delay, behavioral issues, and dysmorphic facial features, and less frequently, microcephaly and seizures
Organizer
Steven Farrell
Organizer
Ogden, UT