NEW YORK (GenomeWeb) – Next-generation sequencing approaches can diagnose inherited bone marrow failure syndromes, according to a new study.
Diagnosis of such syndromes — which include Fanconi anemia, Diamond-Blackfan anemia, and dyskeratosis congenitaiagnosis — is typically based upon hematological and physical findings, though there are some disease-specific diagnostic tests. However, clinical and lab findings for these various conditions often overlap, suggesting that a different approach might be beneficial.
Nagoya University Graduate School of Medicine's Seiji Kojima and his colleagues used targeted sequencing as a first-line diagnostic test for 121 patients with an inherited bone marrow failure syndrome (IBMFS), and used exome sequencing to diagnose 250 others with IBMFS. As they reported in Genetics in Medicine today, the researchers found that 44 percent of patients could be diagnosed with targeted sequencing and 27 percent with exome sequencing.
"Our results demonstrate the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS in clinical practice," they wrote.
Kojima and his colleagues performed targeted sequencing — aimed at 184 disease-linked genes — on 121 consecutive patients clinically diagnosed with IBMFS at Nagoya University Hospital. None of these patients had undergone any other genetic tests.
Through this, they uncovered some 227 coding variants per patient. Of these, 69 variants were previously reported alleles or were unknown variants that were within known disease-associated genes. They also found pathognomonic copy-number changes in 11 patients.
Overall, they diagnosed 53 of the 121 patients, or 44 percent, with their targeted sequencing approach. The most common genetic diagnosis was Diamond-Blackfan anemia followed by Fanconi anemia.
At the same time, the researchers conducted whole-exome sequencing on a cohort of 250 patients with IBMFS. About three-quarters of these patients couldn't be diagnosed with standard genetic tools, while the remaining quarter did not undergo any other genetic testing.
They uncovered some 19,500 coding variants per patient, including 64 previously reported alleles and 23 unknown variants within known disease-associated genes. This enabled the researchers to genetically diagnose 68 patients, or 27 percent of their cohort. They noted that this lower diagnostic rate for WES, as compared to targeted sequencing, is likely due to the conventional genetic testing that much of the cohort underwent before exome sequencing.
For most of the cases — 85 percent of the diagnosed targeted sequencing group and 93 percent of the WES group — the variants detected supported the patients' clinical diagnoses. But others had discordant results.
For some of these instances, the researchers said that the discordance between clinical and genetic diagnoses could be due to the overlap of clinical phenotypes between IBMFS. For example, patient UPN-355 was diagnosed clinically with congenital hemolytic anemia but genetically with congenital dyserythropoietic anemia. Meanwhile, patients UPN-216 and UPN-485 had clinical diagnoses of congenital dyserythropoietic anemia but genetics ones of congenital hemolytic anemia. Both those conditions are marked by hemolysis, the researchers noted.
This, the authors noted, indicates that next-generation sequencing could be a useful tool for clinically diagnosing IBMFS. "Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS," they wrote.