The Emerging Landscape of the Inherited Bone Marrow Failure Syndromes in Mexico

Introduction: Inherited Bone Marrow Failure Syndromes (IBMFS) encompass a diverse group of disorders characterized by bone marrow failure, physical abnormalities, and increased risks of hematologic and solid tumors. The IBMFS are caused by germline pathogenic variants (PVs) impairing the maintenance of the hematopoietic stem and progenitor cells (HSPCs), and therefore the normal production of blood. PVs causing IBMFS may impair effective DNA repair, telomere maintenance, ribosomal assembly, or protein synthesis.

Diagnosing IBMFS is challenging due to their overlapping clinical features. In Mexico this difficulty is increased by the limited access to molecular testing. To address these diagnostic challenges, we have initiated the Mexican Registry of IBMFS, developed in collaboration with geneticists, hematologists, and oncologists from various regions of the country. This registry aims to enhance diagnostic awareness of IBMFS among physicians, facilitate access to genetic testing, refine diagnostic criteria, and support the implementation of personalized treatments.

Objective: To report the genetic etiologies from a cohort of Mexican patients clinically suspected of having IBMFS who underwent germline genetic testing.

Methods: This multicentric observational study involves voluntary enrollment of patients through both in-person and electronic interactions, supported by a nationwide network of medical specialists. Participants are individuals of any age who presented with symptoms suggestive of IBMFS during their pediatric age, documented during initial evaluation, sociodemographic, clinical and laboratory findings. Informed consent was obtained prior to collecting peripheral blood and bone marrow samples for next generation sequencing, including a targeted IBMFS panel with coverage for 116 genes and whole exome sequencing (WES), and subjected to sequencing using an Illumina platform. Patients with FA were excluded from this effort since a well-established chromosome breakage test already exists in Mexico. Telomere length was also assessed through PCR.

Results: This cohort has successfully enrolled patients from diverse regions within Mexico (n = 56). DNA was extracted from peripheral blood or bone marrow. We have identified bona fide PVs causing IBMFS in twelve patients. Dyskeratosis congenita (DC) causing PVs were found in three patients: RTEL1 (heterozygous), DKC1 (hemizygous) and TINF2 (heterozygous), the latter patient was also identified through PCR as having short telomeres. Severe congenital neutropenia (SCN) causing PVs were found in three patients: JAGN1 (homozygous), WAS (hemizygous) and ELANE (heterozygous). A PV causing Swachmann-Diamond Syndrome (SDS) was identified in one patient: SBDS (homozygous). Diamond-Blackfan anemia (DBA) causing PVs were found in four patients: RPS24 (heterozygous) and RPS26 (heterozygous) and two different heterozygous PVs in RPL5 in two different patients. Thrombocytopenia with absent radii (TAR) was confirmed in a single patient with the combination of 1q21.1 deletion and hypomorphic allele in the RBM8A gene. Two more patients, with VUS in the SOS2 and PTPN11 genes, are under further scrutiny for confirmation of Noonan Syndrome. One patient was found to have Transcobalamin II deficiency (homozygous PVs in TCN2 gene), an inherited metabolic disease, and one more patient who coursed with anemia was found to have heterozygous PV in the PUF60 gene, causing Verheij syndrome, a non-IBMFS. Molecular testing for additional 40 patients is currently ongoing, with recruitment efforts still active.

Conclusions: We present the preliminary results of the first, and ongoing effort, to characterize the landscape of PVs causing IBMFS in Mexico. We have identified patients with classic IBMFS, including DC, DBA, SDS, SCN and TAR, as well as other entities that might also course with cytopenias.

No relevant conflicts of interest to declare.