Reinvestigation of unidentified causative variants in FXI-deficient patients: Focus on gene segment deletions.
Haemophilia
; 29(1): 248-255, 2023 Jan.
Article
en En
| MEDLINE
| ID: mdl-36195107
ABSTRACT
INTRODUCTION:
Data on failure to identify the molecular mechanism underlying FXI deficiency by Sanger analysis and the contribution of gene segment deletions are almost inexistent. AIMS ANDMETHODS:
Prospective and retrospective analysis was conducted on FXI-deficient patients' DNA via Next Generation Sequencing (NGS), or Sanger sequencing and Multiplex Probe Ligation-dependent Assay (MLPA) to detect cryptic causative gene variants or gene segment deletions.RESULTS:
Sanger analysis or NGS enabled us to identify six severe and one partial (median activity 41 IU/dl) FXI deficient index cases with deletions encompassing exons 11-15, the whole gene, or both. After Sanger sequencing, retrospective evaluation using MLPA detected seven additional deletion cases in apparently homozygous cases in non-consanguineous families, or in previously unsolved FXI-deficiency cases. Among the 504 index cases with a complete genetic investigation (Sanger/MLPA, or NGS), 23 remained unsolved (no abnormality found [n = 14] or rare intronic variants currently under investigation, [n = 9]). In the 481 solved cases (95% efficiency), we identified F11 gene-deleted patients (14 cases; 2.9%). Among these, whole gene deletion accounted for four heterozygous cases, exons 11-15 deletion for five heterozygous and three homozygous ones, while compound heterozygous deletion and isolated exon 12 deletion accounted for one case each.CONCLUSION:
Given the high incidence of deletions in our population (2.9%), MLPA (or NGS with a reliable bioinformatic pipeline) should be systematically performed for unsolved FXI deficiencies or apparently homozygous cases in non-consanguineous families.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Deficiencia del Factor XI
Límite:
Humans
Idioma:
En
Revista:
Haemophilia
Asunto de la revista:
HEMATOLOGIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Francia