One gene provides diagnoses for 30 patients whose condition was unexplained for years

“The story of our findings began with a patient I saw in the clinic who presented with an unusual combination of problems,” said first and co-corresponding author Dr. Daniel Calame, instructor of child neurology and developmental neuroscience at Baylor. “The patient had severe developmental disabilities, epilepsy and complete insensitivity to pain, which was highly atypical. The condition had gone undiagnosed despite numerous tests performed by geneticists and neurologists.”

Calame enrolled the patient in the BCM GREGoR (Genomics Research to Elucidate the Genetics of Rare Diseases) research program. “We reanalyzed the patient’s genetic and clinical data and that led us to a gene, FLVCR1and a medical mystery to solve,” Calame said.

One gene, multiple conditions

To try to understand how it is rare FLVCR1 mutation in the patient could lead to the condition, Calame and his colleagues examined the scientific literature on this gene. Current evidence indicates that the FLVCR1 protein plays a key role in red blood cell production and in the transport of choline and ethanolamine into cells. Choline and ethanolamine are important for cells. They are precursors to phosphatidylcholine and phosphatidylethanolamine, respectively, which are required for cell membrane integrity needed to support cell division and other essential cellular functions.

Other researchers have the Flvcr1 gene, the equivalent of the human gene, on animal models. They found that knocking out the gene in mice was fatal at the embryonic stage. “The embryos have many bone deformities in the head and limbs and defective red blood cell production, reminiscent of Diamond-Blackfan anemia (DBA) in humans,” Calame said. “But this was different from what we saw in our patient.”

Patients with DBA also have bone deformities. Interestingly enough, although the evidence in mice pointed to it FLVCR1 Because the gene was the gene that caused DBA, it was not determined at the time that the gene played a role in DBA patients. Other genes were discovered that caused the condition.

In addition, other studies found rare defective specimens of the FLVCR1 gene in patients with childhood- or adult-onset ataxia, a condition characterized by poor muscle control and coordination disorders, who also had sensory problems and retinitis pigmentosa, or progressive vision loss. These problems were also not like those Calame saw in his patient.

“We were intrigued. On the one hand, we had a patient with a rare condition FLVCR1 mutation and severe developmental disorders, epilepsy and complete insensitivity to pain, but on the other hand there were patients with rare mutations on the same gene who showed a different set of problems,” said Calame. “Could it be that those different mutations of FLVCR1 caused not one set, but a spectrum of characteristics that we observed in all patients together?”

Solving the mystery of FLVCR1 brings answers for patients

The team looked for an answer to this mystery by combining two strategies. One strategy was to increase the number of patients they could study by identifying individuals with undiagnosed neurodevelopmental disorders FLVCR1 gene variants in large, specialized data sets. They identified the patients through the Baylor-Hopkins Center for Mendelian Genomics/BCM GREGoR database, the Baylor Genetics clinical diagnostic laboratory database, GeneMatcher, or other research and clinical diagnostic laboratories.

“We identified 30 patients from 23 unrelated families with rare diseases FLVCR1 variants,” Calame said.

The researchers found 22 gene variants, 20 of which had not previously been described. The characteristics of the patients range from severe developmental disorders with major developmental delay, microcephaly (a head that is much smaller than expected), brain malformations, epilepsy and premature death. Severely affected patients share features including anemia and bone deformities, while mice do not Flvcr1 gene and DBA, which was not linked FLVCR1 for.

The second strategy to find an answer to this medical mystery was to characterize the functional consequences of the disease FLVCR1 variants in laboratory experiments in collaboration with Dr. Long Nam Nguyen and colleagues from the Yoon Long Lin School of Medicine, National University of Singapore. The team wanted to better understand what effect the different variants they found in patients would have on the transport of choline and ethanolamine in cells in the laboratory. They found that FLVCR1 variants significantly reduce choline and ethanolamine transport – up to half the transport seen with normal FLVCR1 proteins. “We propose that the severity of the disease depends on the residual transport activity of the FLVCR1 variants that a patient carries,” Calame said.

Other studies have shown that choline is necessary for normal neurological development and that its deficiency also causes anemia, liver disease, growth retardation and immune deficiency. “Neurodevelopment is also disrupted by defective choline absorption, and we have shown that the variants reduce choline transport in our patients,” Calame said.

Taken together, the findings show that FLVCR1 variants cause a broad spectrum of developmental problems, ranging from severe multiorgan developmental defects similar to DBA to adult-onset neurodegeneration. The variants identified in patients reduce the transport of choline and ethanolamine in cells in the laboratory, indicating that the transport of these molecules to the central and peripheral nervous systems is essential to prevent neurodegeneration and is required for normal neurological development.

“Our findings also support further studying the potential therapeutic value of choline or ethanolamine supplementation FLVCR1-related diseases,” Calame said. “The 30 patients we identified had not been diagnosed for years; It was worth being able to provide an explanation for their condition.”

This study also underlines the importance of approaching the diagnosis of rare diseases from a broad perspective. “The 30 severely affected individuals reported here all had undergone clinical or research exome or genome sequencing, which increases the reported FLVCR1 variants, but in each case the variants were more likely to be perceived as non-contributory or of uncertain significance given the apparent discrepancy of characteristics in patients,” Calame said. Such false assumptions illustrate the importance of including model organism data in personalized genome analysis for rare diseases. diseases and the need to anticipate more severe and milder patient characteristics associated with each disease gene to maximize the yield of diagnostic genetic testing.”