Next-generation sequencing to analyze a panel of 11 specific genes may facilitate the diagnosis of amyloidosis, including familial amyloid polyneuropathy (FAP), according to researchers from the Czech Republic.
The new approach was described in the study, “Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing,” published in the Journal of Clinical Pathology.
Amyloidosis is a rare condition characterized by the deposition of abnormal proteins in tissues, causing the destruction of their natural structures, and impairing their function. A total of 27 human proteins have been identified that have the potential to cause amyloidosis.
Its low incidence, occurring in 10 out of one million people, makes it difficult to promptly identify, leading to treatment delays. This need for better diagnostic methods is especially true in hereditary amyloidosis, or FAP, because it requires a more detailed knowledge about these genetic diseases by physicians.
Genetic mutations in one of seven genes — TTR, FGA, APOA1, APOA2, LYZ, GSN, and CST3 — have been linked to the formation of amyloid deposits in the heart, liver, gastrointestinal (GI) tract, kidneys, and the central nervous system.
To improve the diagnosis of FAP, a team led by researchers at the University of Ostrava in the Czech Republic developed a new method that could allow for the straightforward and simultaneous testing of all related mutations.
The researchers used next-generation sequencing to screen all 11 related genes in 40 patients with hypertrophic cardiomyopathy — a nonspecific heart impairment that is often present in cardiac amyloidosis — of unknown origin.
After a computer analysis of the large-scale data, the team identified one patient who had a TTR gene variant that could cause FAP. The variant he had, identified as Glu82Lys, is very rare — this was just the second time it was described in a patient.
Although the cardiac symptoms could be easily misdiagnosed, the genetic characterization and a complete diagnostic workflow confirmed the patient had late-onset ATTR amyloidosis, or FAP.
They also identified another patient who missed a small coding sequence of the PRNP gene. A similar deletion had been previously linked to Alzheimer’s disease, which is one of the most frequent types of amyloidosis in humans.
The proposed diagnostic method can also be used to identify new potentially harmful genetic variants associated with amyloidosis, the researchers said.
They could find a new genetic mutation on the B2M gene that was located in a region that could potentially affect the coded protein function, leading to FAP. However, additional studies would be needed to further confirm this hypothesis.
“Rare hereditary diagnoses are especially suitable for screening by next generation sequencing,” the researchers said. This strategy allows for the “examination of larger genomic regions” compared to standard sequencing methods.
Also, it allows for the analysis of tens of genes at the same time with considerably “less money and with less effort.”