Unveiling the Clinicopathological and Molecular Spectrum of Fanconi Anaemia: Insights from a Single-Centre Experience

Saima  Siddiqui; Ikram din  Ujjan; Shariq  Ahmed; Danish  Zahid; Safia Mehmood  khan; Affaf  Sheikh; Ali  Waryah

doi:10.18502/ijpho.v16i2.21348

Saima Siddiqui National Institute of Blood diseases and Bone Marrow Transplantation, PECHS campus, Pakistan
Ikram din Ujjan Liaquat University of Medical and Health Sciences (LUMHS), Deh Soun Valhar,, Jamshoro, Sindh, Pakistan
Shariq Ahmed National Institute of Blood diseases and Bone Marrow Transplantation, PECHS campus, Pakistan
Danish Zahid National Institute of Blood diseases and Bone Marrow Transplantation, PECHS campus, Pakistan
Safia Mehmood khan National Institute of Blood diseases and Bone Marrow Transplantation, PECHS campus, Pakistan
Affaf Sheikh National Institute of Blood diseases and Bone Marrow Transplantation, PECHS campus, Pakistan
Ali Waryah Liaquat University of Medical and Health Sciences (LUMHS), Deh Soun Valhar,, Jamshoro, Sindh, Pakistan

DOI: https://doi.org/10.18502/ijpho.v16i2.21348

Keywords: Fanconi anaemia, FANCA, Inherited bone marrow failure, Next-generation sequencing.

Abstract

Background: Fanconi anaemia (FA) is the most common cause of constitutional bone marrow failure. The pathophysiology of this disease is highly complex and still unclear. It is caused by a mutation/pathogenic variant in any of the 22 complementation groups that work together in the DNA damage repair mechanism. Approximately three-fourths of FA cases are due to defects in the FANCA gene. This study investigates the molecular and clinicopathological profiles of FA patients.

Materials and Methods: This prospective observational study screened 780 aplastic anaemia patients using chromosomal breakage analysis, and the results were positive for 60 patients, therefore labeled as FA. Baseline biodata and clinical and laboratory parameters were recorded via a questionnaire. In this study, Samples from the first 50 patients were screened for c.378803790delTCT through PCR RFLP, which revealed its presence in one patient. Ten additional samples were also screened via next-generation sequencing (NGS) for broader genetic analysis.

Results: The median age of the patients was 11.5 years (IQR 5 years), with the majority (68%) of the participants being male. Growth retardation and pancytopenia were present in 98.3% and 95% patients, respectively. A total of 20 variants were detected (2 via RFLP and 18 via NGS). Seventeen were pathogenic variants, of which 16 (80%) affected FANCA and 20% affected FANCG. Twelve variants (74%) in FANCA were deletions. c.3788-3790delTCT was detected in 3 out of 60 patients (1 through RFLP and the other 2 through NGS).

Conclusion: FA is a clinically and genetically heterogeneous disease. Patients presenting with cytopenia combined with growth retardation and somatic abnormalities should be suspected of having FA. Genetic diagnosis is necessary for confirmation. NGS can aid in the diagnosis and subtyping of patients in whom targeted/hotspot mutations are unknown.