An international team of researchers has identified the genetic variants responsible for a previously undiagnosed condition primarily affecting the nervous system. The study, based on data from an undiagnosed patient who visited one of the researchers, has helped identify other patients with mutations in the same gene and potential therapeutic targets for this rare genetic disease.
Dr. Daniel Calame, a researcher at the Department of Pediatrics at Baylor College of Medicine and the lead author of the study, stated, "The story of our findings began with a patient I saw in the clinic who presented a rare combination of issues." The patient exhibited severe developmental problems, epilepsy, and complete insensitivity to pain, which were atypical. The disease had gone undiagnosed despite numerous tests conducted by geneticists and neurologists.
Diagnosing a rare disease, especially in genetic disorders affecting the nervous system, can be a significant challenge for both patients and healthcare professionals due to the great heterogeneity of symptoms. While some cases are diagnosed through genetic studies, many mutations are so rare that they go unnoticed, significantly delaying diagnosis.
The work, published in the journal Genetics in Medicine, achieved genetic diagnosis for Dr. Calame's patient and another 29 patients who had previously been undiagnosed. To establish the connection between the gene and the patients' rare disease, Dr. Calame collaborated with specialists from Baylor College of Medicine, the National University of Singapore, and other global institutions.
In their investigation, Dr. Calame and his team analyzed the genome of the patient to identify genetic mutations that could explain the clinical phenotype. This led them to the gene FLVCR1 and a clinical mystery to solve.
The FLVCR1 gene, located on chromosome 1, plays a crucial role in the production of erythrocytes and the transport of two important molecules (choline and ethanolamine) within cells. Various studies have shown that choline is essential for the development of the nervous system, and its deficiency can lead to anemia, liver disease, and immune deficiency.
Evidence indicates that loss of function of the FLVCR1 homolog in mouse models is lethal during early development. However, the malformations observed in mouse embryos differ significantly from those presented by Dr. Calame's patient. "Mouse embryos exhibit bone malformations in the head and extremities and defective red blood cell production, reminiscent of Diamond-Blackfan anemia in humans, but this was different from what we observed in our patient," explained Calame.
Other studies linked mutations in FLVCR1 with early development of ataxias (muscle control deficiencies), a condition not exhibited by Calame's patient. "We were intrigued. On one hand, we had a patient with a rare mutation in FLVCR1 and severe developmental disorders, epilepsy, and total insensitivity to pain, yet on the other hand, there were patients with rare mutations in the same gene presenting a different set of issues," explained Dr. Calame.
To resolve the mystery of the symptom heterogeneity related to FLVCR1 mutations, the team sought other patients in similar situations within large genomic databases. They analyzed data from the Baylor-Hopkins Center for Mendelian Genomics and the Baylor Genetics Clinical Diagnostic Laboratory, among others, allowing them to identify 29 new patients with 22 different rare variants in FLVCR1.
The characteristics and symptoms of these patients were quite heterogeneous: severe developmental disorders, microcephaly, brain malformations, epilepsy, and premature death, among others. However, all severely affected patients shared traits such as anemia or bone malformations.
In a second phase of the study, Dr. Calame's team analyzed the molecular mechanisms related to FLVCR1 in cell models with mutations in this gene. They collaborated with Dr. Lon Nam Nguyen's lab at the National University of Singapore.
Together, the research teams studied the cellular effects of the mutations found in the 30 participating patients. The analysis revealed that genetic variants in FLVCR1 reduce choline and ethanolamine transport by up to 50% within cells. This suggests that the deficit in transporting these two molecules may be related to failures in neurological development and anemia.
This work enhances the understanding of FLVCR1's functions and its effects on choline and ethanolamine transport within cells, as well as its direct impact on 30 individuals with a rare disease who had not previously received a genetic diagnosis.
Dr. Calame explained, "The 30 severely affected individuals mentioned here had undergone clinical or research exome or genome sequencing, which identified the reported FLVCR1 variants, although in each case, these variants were previously considered not contributory or of uncertain significance given the apparent discordance of characteristics among patients."
He added, "These false assumptions illustrate the importance of incorporating model organism data into personalized genomic analysis for rare diseases and the need to anticipate both more severe and milder patient characteristics associated with each disease gene to maximize the yield of diagnostic genetic testing."
The research team also highlighted the therapeutic potential of choline and ethanolamine supplements in patients with genetic variants in FLVCR1. Future studies may confirm whether administering these molecules could be beneficial in alleviating or reversing symptoms in these patients.