Colton spent 30 days in NICU with respiratory and feeding distress. After NICU discharge things at home were going well until at around 9-12 weeks old he began having difficulty eating. Colton ultimately had spent 157 days in the hospital during his first year of life.
Colton became very ill with Respiratory Syncytial Virus (RSV) in October 2021 (when he was 4 months old), where he spent a week in the ICU due to complications. Two days after our return home we noticed Colton starting to do these “twitches”. We immediately brought him back to hospital where he was hooked up to an electroencephalogram (EEG). After a 24 hour scan the neurologist told us that it was likely just developmental “hiccups”. We were sent home with a suggested follow up the following month.
Colton's twitches increased from 3-5 times a day to over a hundred. In our follow up with a neurologist they told us that he would grow out of the twitches and likely something bigger is the issue. We were disappointed in the response because it just didn’t seem right, especially as our other children never presented that way. These twitches continued to progress until our worst day. At the end of November 2021 our whole family had Covid, including Colton. Surprisingly though, Colton had the least amount of symptoms.
As my husband Paul and I took turns taking naps and watching the kids, Colton began to have his twitches, but this time they became very violent then Colton went limp and blue in Paul’s arms. It took an ambulance over 30 minutes to get to our home. Once Colton was hooked up to oxygen his colour slowly returned. Once hooked up to another EEG we got our devastating diagnosis. Not only was Colton having a seizure, his EEG was significantly worse than it was just a month and a half prior. The same doctor who told us not to worry came to tell us that he has infantile spasms and to prepare for a difficult life ahead.
We went months trying to figure out the right medications, all while Colton fought illness after illness. Colton's status seizures always came in conjunction with a respiratory illness. After getting the rhinovirus (common cold) that sent him to month-long hospital stays and several intubations. We demanded for more tests to be done to better understand what was going on.
Colton was diagnosed with CRELD1 in February 2022. Colton's diagnoses have accumulated over the last year and include infantile spasms/ epilepsy, status epileptics, adrenal insufficiency, failure to thrive, low tone, global developmental delay, moderate to severe bilateral neural hearing loss, G-J placement and eats through J port, submucosal cleft palate, immature eye development, and acute respiratory distress/failure.
Colton had a port-a-catheter placed at 12 months due to difficult IV placements. He has been admitted to PICU several times and has had three emergency intubations for both seizure and pulmonary causes and several respiratory illnesses over his first year of life.
Due to Colton picking up so many illnesses, he had an immunology panel test done to better understand the level of his immune function. Colton’s IGG and IGB numbers were found to be extremely low - basically his body doesn’t remember when he’s had an illness and so he can’t build immunity because he can’t keep those good cells around. Colton was started on Intravenous Immunoglobulin (IVIg) infusions once a month to help boost his immune system. It's very early days, but Colton has had a positive response to the infusions, in terms of more energy and alertness. We are hoping to see more positive results for Colton with his IGG levels as the infusions continue.
Despite this list of difficulties, Colton is the strongest, most resilient boy we’ve ever met. He smiles and coos, loves to hold our hands and be snuggled. He is adored by his three older siblings. There is no greater love or commitment to creating a pleasurable and positive atmosphere by our family. He - along with the other CRELD1 Warriors - bring absolute joy to our lives. This has been an incredibly difficult year and we couldn’t have done it without the support of our other parents.
Colton's genetics results
Sequencing analysis has shown that Colton is heterozygous for two variants of uncertain significance in the CRELD1 gene. While the CRELD1 gene is typically associated with autosomal dominant inheritance, autosomal recessive inheritance has also been suggested.
c.959del:p.(GIn320Argfs*25) in exon 9 of the CRELD1 gene (NM_015513.4). The normal sequence with the base(s) that are altered in brackets is: AAGC[delA]GTGT
The proband's father (GeneDx #2390779) is heterozygous for the p.(Q320Rfs*25) variant in the CRELD1 gene.
Identified in an individual with seizures who also harbored a second CRELD1 variant in published literature.
Frameshift variant predicted to result in protein truncation as the last 101 amino acids are lost and replaced with 24 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein.
Observed in 84/282702 (0.0297%) alleles in large population cohorts (gnomAD)
We interpret this as a Variant of Uncertain Significance.
p.(Cys192Tyr) (TGT>TAT): c.575 G>A in exon 5 of the CRELD1 gene (NM_015513.4)
The proband's mother (GeneDx #2390769) is heterozygous for the p.(C192Y) variant in the CRELD1 gene. The proband's father (GeneDx #2390779) does not harbor the p.(C192Y) variant in the CRELD1 gene.
Identified in an individual with seizures who has also harbored a second CRELD1 variant in published literature
Observed with a likely pathogenic variant on the opposite allele (in trans) in a patient with seizures, poor vision, and hypotonia referred for genetic testing at GeneDx
Observed in homozygous state in a patient referred for genetic testing at GeneDx with failure to thrive, Microcephaly, and seizures and not observed in homozygous state in controls
In silico analysis supports that this missense variant has a deleterious effect on protein structure/ function
Observed in 52/282700 (0.0184%) alleles in large population cohorts (gnomAD)
We interpret this as a Variant of Uncertain Significance.
https://www.creld1.com/colton-s-story
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Abstract
Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants.
Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells.
Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors.
Conclusion: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.
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