Unveiling Mysteries: Novel Germline Mutations in Children with Bone Marrow Failure Syndrome and Hematologic Malignancy of Arab Ancestry
Authors: Abu Shanap Mayada , Sultan Iyad 
Published: December 2024

Introduction : Inherited predisposition to Hematologic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. We sought to study genetic of Cancer predisposition and or bone marrow failure genes in children treated at King Hussein Cancer Center.

Methods: This is a retrospective review of patients who were referred to our Cancer Predisposition clinic that was established in Jan 2020. Referred patients were screened using Jongmans' and McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) for cancer predisposition. Next-generation sequencing of germline DNA was performed using panels of genes suited for patients' diagnosis and family history.

Results: 103 patients were screened; all were under age of 18-years .Most of patients fulfilled Jongmans' and/or MIPOGG criteria; sixty patients (58%) had family history of cancer, congenital or other phenotypic anomalies were detected in 45 patients with inherited bone marrow failure syndrome (IBMFS), five patients were referred due the diagnosis of two malignancies, excessive toxicity related to cancer treatment was reported in 10 patients. Primary Hematological malignancies were diagnosed in 58 patients : ALL (n=17), AML (n=11), Myelodysplastic (MDS)/ myeloproliferative diseases (MPD) (n=8) and lymphomas (n=22 ).

Pathogenic/Likely pathogenic germline mutations were identified in 25 patients (43%), VUS /likely causative in 27 patients (47% ) with hematologic malignancy across the cancer predisposition (CPS) genes as following: CPS genes in ALL( MSH6,PTCH1,TP53, MET, CDH1, POLE, ERCC6L2, RUNX1, RAD50, ATM, SDHA, RABGAP1, POT1, VHL). CPS genes in AML( ACD, GATA2, MUTYH, BPTF,FANCA, FANCG, HAX1,ELANE and mitochondrial DNA deletion ~5kb in Pearson syndrome). CPS genes in MDS/MPD ( NF1, PTPN11, VPS45, GATA2, ACD,DUT, FANCG, ELANE). CPS genes in Lymphoma(RASGRP1, BRCA1, CHEK2, ATM, MSH3,TNFRSF9, PTCH1, MSH6, NAF1, CASR, DCLRE1C, RASGRP1, RIPK1, ATM, BRCA2, ERBIN, STK4, DOCK8).

Pathogenic/Likely pathogenic germline mutations were identified in 36 patients (82%), VUS /likely causative in 8 patients (18%) with IBMFS as following: Fanconi Anemia (FANCA,FANCD2,FANCF,FANCG) Diamond-Blackfan anemia(RPL11, RPS19, RPL5, RPL35A), Dyskeratosis congenita (TINF2, PARN), Shwachman-Diamond Syndrome (SBDS), Severe congenital neutropenia(CSF3R), ERCC6L2 Syndrome (ERCC6L2), Adenosine Deaminase 2 deficiency( ADA2),CBL Syndrome(CBL), Epimerase deficiency galactosemia (GALE), Ghosalhemato diaphyseal dysplasia (TBXAS1),Idiopathic Bone marrow failure ( ALPK3), Bone Marrow Failure Syndrome 4 (MYSM1),THPO-Hereditary Thrombocytopenia (THPO),TUBB1-related Macrothrombocytopenia ( TUBB1), X-linked recessive Wiskott-Aldrich syndrome (WAS).

Conclusion: By screening our patients carefully, we were able to identify a significant number of patients with cancer predisposition Syndrome. The early recognition of genetic predispositions for childhood cancers may provide an opportunity of therapy adjustment and specific screening for different syndrome-related malignancies as well as genetic counseling. Further refinement of our testing may require WES to detect structural variations and collaboration with research centers to perform functional testing for patients with VUS.