A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects

George, Merin; Solanki, Avani; Chavan, Niranjan; Rajendran, Aruna; Raj, Revathi; Mohan, Sheila; Nemani, Sandeep; Kanvinde, Shailesh; Munirathnam, Deendayalan; Rao, Sudha; Radhakrishnan, Nita; Lashkari, Harsha Prasada; Ghildhiyal, Radha Gulati; Manglani, Mamta; Shanmukhaiah, Chandrakala; Bhat, Sunil; Ramesh, Sowmyashree; Cherian, Anchu Anna; Junagade, Pritesh; Vundinti, Babu Rao

doi:10.1002/humu.24286

Cited by 6 publications

(6 citation statements)

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“…There were 14 different deletions in 20 patients. As reported in a previous Indian population study,22 we also observed a high frequency of FANCA exon 27 deletion (3.6%) in our patients (online supplemental figure S3B, table 1). FANCC , the second frequently mutated gene with a frequency of 10%–15% in other populations,20 22 was rare (1.5%) in our patients.…”

Section: Resultssupporting

confidence: 90%

“…As reported in a previous Indian population study,22 we also observed a high frequency of FANCA exon 27 deletion (3.6%) in our patients (online supplemental figure S3B, table 1). FANCC , the second frequently mutated gene with a frequency of 10%–15% in other populations,20 22 was rare (1.5%) in our patients. The frequency of FANCG pathogenic variants was comparable with other populations (11.7% in this study vs 9%–12% in other populations) 2 36.…”

Section: Resultssupporting

confidence: 90%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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BackgroundFanconi anaemia (FA) is a rare inherited bone marrow failure disease caused by germline pathogenic variants in any of the 22 genes involved in the FA-DNA interstrand crosslink (ICL) repair pathway. Accurate laboratory investigations are required for FA diagnosis for the clinical management of the patients. We performed chromosome breakage analysis (CBA), FANCD2 ubiquitination (FANCD2-Ub) analysis and exome sequencing of 142 Indian patients with FA and evaluated the efficiencies of these methods in FA diagnosis.MethodsWe performed CBA and FANCD2-Ub analysis in the blood cells and fibroblasts of patients with FA. Exome sequencing with improved bioinformatics to detect the single number variants and CNV was carried out for all the patients. Functional validation of the variants with unknown significance was done by lentiviral complementation assay.ResultsOur study showed that FANCD2-Ub analysis and CBA on peripheral blood cells could diagnose 97% and 91.5% of FA cases, respectively. Exome sequencing identified the FA genotypes consisting of 45 novel variants in 95.7% of the patients with FA.FANCA(60.2%),FANCL(19.8%) andFANCG(11.7%) were the most frequently mutated genes in the Indian population. AFANCLfounder mutation c.1092G>A; p.K364=was identified at a very high frequency (~19%) in our patients.ConclusionWe performed a comprehensive analysis of the cellular and molecular tests for the accurate diagnosis of FA. A new algorithm for rapid and cost-effective molecular diagnosis for~90% of FA cases has been established.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“… 11 FANCA, FANCG, and FANCC have been found to be common FA complementation groups. 12 In around 60 to 70% patients diagnosed with FA, FANCA gene mutation predominates. These mutations may be insertion or deletion which may lead to premature termination or large deletions and null mutations.…”

Section: Geneticsmentioning

confidence: 99%

A Narrative Review on Fanconi Anemia: Genetic and Diagnostic Considerations

Sharma

2022

Glob Med Genet

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Fanconi anemia (FA) is an autosomal recessive disorder, both genetically and phenotypically. It is characterized by chromosomal instability, progressive bone marrow failure, susceptibility to cancer, and various other congenital abnormalities. It involves all the three cell lines of blood. So far, biallelic mutations in 21 genes and one x-linked gene have been detected and found to be associated with FA phenotype. Signs and symptoms start setting in by the age of 4 to 7 years, mainly hematological symptoms. This includes pancytopenia, that is, a reduction in the number of white blood cells (WBCs), red blood cells (RBCs), and platelets. Therefore, the main criteria for diagnosis of FA include skeletal malformations, pancytopenia, hyperpigmentation, short stature, urogenital abnormalities, central nervous system, auditory, renal, ocular, and familial occurrence. Patients showing signs and symptoms of FA should be thoroughly evaluated. A complete blood count will reveal a reduced number of RBC, WBC, and platelets, that is, pancytopenia. Chromosomal breakage study/stress cytogenetics should be done in patients with severe pancytopenia. Momentousness timely diagnosis of current disease, prenatal diagnosis, and genetic counseling should be emphasized.

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“…[3,4] FANCL is just one of the FA complementation (FANC) genes, which include a total of 22 genes, namely FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCR, FANCS, FANCT, FANCU, FANCV, and FANCW. [5][6][7] Researches have reported that heterozygous mutations in the FANC genes may lead to an increased susceptibility to tumors and acquired BMF. [8][9][10][11] However, there is currently no literature reporting the relationship between FANCL heterozygous mutation and the onset of acquired BMF.…”

Section: Introductionmentioning

confidence: 99%

An acquired BMF with FANCL gene heterozygous mutation: Case report

Zhang¹,

Xiao²,

Miao³

et al. 2023

Medicine

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Rationale: Bone marrow failure (BMF) includes inherited and acquired BMFs. Acquired BMF can be secondary to various factors, such as autoimmune dysfunction, benzene, drugs, radiation, viral infection and so on. Fanconi anemia (FA) complementation group L (FANCL) is an E3 ubiquitin ligase that participates in the repair of DNA damage. Homozygous or compound heterozygous mutations of FANCL can lead to the onset of FA, which is one of the most common inherited BMFs.Patient concerns and Diagnoses: Here, we report a case of acquired BMF. This patient had a history of benzene exposure for half a year before the onset of the disease, and presented with progressive pancytopenia, especially the reduction of erythrocytes and megakaryocyte, without malformation. Interestingly, this patient and his brother/father had a heterozygous (non-homozygous/compound heterozygous) mutation (Exon9, c.745C > T, p.H249Y) in the FANCL gene. Interventions and Outcomes:The patient successfully underwent unrelated and fully compatible umbilical cord blood hematopoietic stem cell transplantation.Lessons subsections: We report for the first time an acquired BMF case with FANCL gene heterozygous mutation, and the mutation site (Exon9, c.745C > T, p.H249Y) has never been reported. This case suggests that heterozygous mutations in FANCL gene may be associated with increased susceptibility to acquired BMF. Based on current reports and this case, we speculate that heterozygous mutations in the FA complementation gene may exist in a certain proportion of tumor and acquired BMF patients, but have not been detected. We recommend routine screening for FA complementation gene mutations in tumor and acquired BMF patients in clinical practice. If positive results are found, further screening can be conducted on their families.

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A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects

Cited by 6 publications

References 73 publications

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

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

A Narrative Review on Fanconi Anemia: Genetic and Diagnostic Considerations

An acquired BMF with FANCL gene heterozygous mutation: Case report

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