First Description of New Variant of Germline ERCC6L2 Mutations Causing Bone Marrow Failure, a Single Center Report of 11 Cases in 7 Families
Authors: Haroon Alfadil , Aljefri Abdullah , Jaradi Mohamed , Alotaibi Ahmad S. , Alfayez Mansour , Alzahrani Hazza , Almohareb Fahad , Alahmari Ali D , Saad Ayman , Rasheed Walid , Alsharif Fahad Z. , Chaudhri Naeem A. , Khogeer Haitham A. , Alsuwaidan Abdullah , Aljurf Mahmoud , Ahmed Syed Osman 
Published: December 2024

Introduction:
Excision repair cross-complementing 6 like 2 (ERCC6L2) , an ATP-dependent DNA translocase, located on chromosome 9 (9q 22.32) spanning 14 exons. Recently, it has been reported that biallelic variation in ERCC6L2 causes bone marrow failure(BMF), myeloid malignancies, and neurological impairment.Additionally, it modulates the mitochondrial function, elevate levels of reactive oxygen species and perturbing cellular homeostasis.High effect size germline variation associated with BMF syndrome, including clinical implications because of height risks to progress to Acute Myeloid Leukaemia (AML)/Myelodysplastic Syndrome (MDS) with or without mutated clones of TP53 and Monosomy 7.
The hematological profile of BMF due to ERCC6L2 consists of trilineage cytopenia, which includes neutropenia with counts ranging from 100 to 1600/μL, anemia with hemoglobin levels ranging from 7.0 to 12.7 g/dL, and thrombocytopenia with initial platelets values ranging from 4 to 166 x 109/L. Hypocellular bone marrow was observed, either with or without dysplastic features. Non-hematological features include neurological dysfunctions, dysmorphic features , skin rash and developmental delay.
To our knowledge, ERCC6L2 related BMFS has been identified in only 35 families globally. Within these cases, 19 distinct variants of the ERCC6L2 gene have been documented. To date, there is limited literature describing their underlying biological mechanisms and clinical implications of these germline variants in affected individuals and families. We present data from 11 cases in 7 Saudi families with ERCC6L2 mutations.
Method:
Clinical data extracted from the inherited marrow failure registry at King Faisal Specialist Hospital and Research Center-Riyadh. Whole-exome sequencing identified the causative mutations.
Result:
Our series consisted of 11 individuals from seven Saudi families.Three patients from family1 ,two in both family 2 and family 3 ,one each in family 4 through 7.The median age was 14 years (range 6-37). There were five females and six males; 10 had homozygous and one had heterozygous ERCC6L2 mutations. workup for other causes of BMF were negative. Among them, five presented with bleeding, 3 with symptoms of anemia, one with neurological manifestations and two were asymptomatic. Anemia was present in 8 patients while, low white blood cell counts were seen in 5 patients, and hypocellular bone marrow was noted in 10 patients. Non-hematological manifestations were seen in one patient with global developmental regression and quadriplegia.This patient was diagnosed with B cell linker protein (BLNK) mutation and primary immunodeficiency with no evidence of large granulocytic leukemia. Out of eleven patients, 2 were diagnosed with hypoplastic MDS, one with MDS/AML and the remaining 8 patients were diagnosed with BMF Syndrome.There were 5 different variants in ERCC6L2. Seven patients (from 3 families) cases of ERCC6L2 c.3370_3771del homozygous mutation variant were diagnosed , while 4 cases of missend different mutations variants (c.2158_2159dup, c.3740_3741del, c.3276dup and c.1987C) were found.Eight patient had normal cytogenetic, while 2 showed mutation of the TP53 gene, and one patient exhibited chromosome 7 monosomy. Three patients underwent MSD hematopoietic stem cell transplantation (HSCT), while 2 were done using MUD and one haploidentical HSCT. Five patients were handled conservatively or with immunotherapy. Three died: one from graft versus host disease, another during the induction chemotherapy, and the last from a septic shock following relapsed AML.
Conclusion:
In our limited series, patients exhibit variable clinical course, while some patients only have mild BMF and a rather mild clinical course, others show more severe hematological disorders such as MDS, AML or BMF required HSCT. HSCT for selected patients such as young age, sever bone marrow aplasia or progressing either to AML or MDS, has resulted in favourable outcome. To our knowledge, none of these five variants of ERCC6L2 have been described earlier. Patients with ERCC6L2 biallelic mutations suggest a very discrete phenotype within this BMFS. New cases offer further opportunities for the investigation of this syndrome of BMF and more detailed exploration concerning the etiology and clinical spectrum.