Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

Abstract

Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. Results: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-yearold. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p = 0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. Conclusions: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis

“…FANCA was the most frequently mutated gene (60.2%) in our study as reported in other populations (60%–80%)2 20 36(online supplemental table S3, figure 2). In the 82 patients with FANCA pathogenic variants, 96 pathogenic variants were identified, out of which 32 were novel.…”

“…Seven of these 12 patients showed defective FANCD2-Ub (58.3%), and subsequent pathogenic variant analysis confirmed them to be FA cases. Defects in the downstream FA pathway genes, which do not affect FANCD2-Ub, are very rare (2%–6 %)4 20 in patients with FA, and we also found the downstream pathogenic variants in only ~2.2% of the Indian patients. Therefore, FANCD2-Ub analysis may be used as a reliable test for the diagnosis of FA.…”

“…Identifying defective genes and pathogenic variants is crucial for carrier detection and prenatal diagnosis of FA in the affected families and genotype-phenotype correlation in the patients. A few whole exome sequencing (WES) studies have been carried out to determine the frequencies of defective genes and the spectrum of mutations in populations 2 20–22. Strong associations between malignancies and biallelic pathogenic variants in FANCD1 / BRCA2 and FANCN / PALB2 7 23–26 and monoallelic pathogenic variants in FANCS / BRCA1 , FANCJ / BRIP1 and FANCO / RAD51C have been established 3 27.…”

“…Strong associations between malignancies and biallelic pathogenic variants in FANCD1 / BRCA2 and FANCN / PALB2 7 23–26 and monoallelic pathogenic variants in FANCS / BRCA1 , FANCJ / BRIP1 and FANCO / RAD51C have been established 3 27. Genotyping a large number of patients from different populations, especially those with high consanguinity rates, helps better comprehend the genotype-phenotype correlation 7 20 28–30. We performed CBA, FANCD2-Ub analysis and exome sequencing of 142 patients with FA from the Indian population and evaluated the efficacy of these methods in diagnosis.…”

Genetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction

“…Our sensors provide a toolkit that may help to improve our understanding of the potential roles of FA in various cellular processes. Some recent research examined Fanconi anemia patients and found that people holding the ALDH2 dominant-negative variant (ALDH2*2) had the tendency of accelerated progression of bone marrow failure (BMF) 48 , 49 . Study on Fancd2 , Aldh2 and Adh5 knockout mice have indicated the effect of increased endogenous formaldehyde in the process 4 , 5 .…”