New SAMD9L heterozygous mutation leading to myelodysplastic syndrome and acute myeloid leukemia: A case report and review of the literature

Abstract Background SAMD9L mutation is linked to the development of myeloid neoplasm. The mutation has a wide range of clinical presentations involving neurological, immunological, and hematological manifestations. Until now, limited data regarding different variants of this genetic mutation existed. Here we present a 6‐year‐old girl who presented with acute myeloid leukemia/myelodysplastic changes and who carries a new germline variant mutation in the SAMD9L gene. Case Presentation A 6‐year‐old girl who presented initially as a case of immune thrombocytopenic purpura (ITP) was later diagnosed with acute myeloid leukemia and myelodysplastic changes. In addition, she was found to have a new germline variant mutation in the SAMD9L gene (other known pathogenic variants known to cause ataxia pancytopenia syndrome). She was treated with chemotherapy followed by haplo identical transplant from her unaffected father. She is alive 30 months post‐transplant and in complete remission with full donor chimerism. Her initial brain MRI showed mild prominence of the anterior (superior) vermis folia, suggesting mild atrophy. Ongoing surveillance for accompanied neurological manifestation is ongoing, although the patient is asymptomatic. Conclusion For SAMD‐9L‐related disorder, a careful approach must be taken when a patient presents with a suspicious clinical feature even without a well‐known genetic mutation giving the diverse presentation across affected members within the same family. In addition, other associated abnormalities should be monitored long‐term.

ant mutation in the SAMD9L gene (other known pathogenic variants known to cause ataxia pancytopenia syndrome). She was treated with chemotherapy followed by haplo identical transplant from her unaffected father. She is alive 30 months posttransplant and in complete remission with full donor chimerism. Her initial brain MRI showed mild prominence of the anterior (superior) vermis folia, suggesting mild atrophy. Ongoing surveillance for accompanied neurological manifestation is ongoing, although the patient is asymptomatic.
Conclusion: For SAMD-9L-related disorder, a careful approach must be taken when a patient presents with a suspicious clinical feature even without a well-known genetic mutation giving the diverse presentation across affected members within the same family. In addition, other associated abnormalities should be monitored long-term. F I G U R E 1 Dot-plot histograms from flow cytometric analysis of the bone marrow aspirate from our patient show SSC/CD45 dim population as the blast (25% cell population in blast region). Blasts (red populations) show positivity for CD13, CD33, CD34, CD38, CD117, CD123, & HLADR with partial expression of CD34; dim expression of CD4 and MPO; partial/dim expression of CD7, CD15 and CD19. The flowcytometric analysis used BD FACSDiva™ Software. CD45 gating was applied (CD45-SSC). Events ranged from 30 000 to 50 000 events; percentages of each population are displayed for selected population of interest in each plot in relation to total population (Total population defined as total numbers of events in the tube of bone marrow sample).

| CASE REPORT
A 6-year-old girl was admitted to our hospital (King Abdul-Aziz Medical City-Jeddah) as a case of pancytopenia for investigations. She had a history of isolated thrombocytopenia for 3 years prior to her presentation. She was treated as a chronic immune thrombocytopenic purpura with intravenous immunoglobulin (IVIG) and observation. She had a febrile illness for 3 weeks before her admission, and her complete blood count (CBC) showed pancytopenia with 7% peripheral blast. Otherwise, her past medical history was unremarkable. She has a 10-year-old sister who is healthy and has no history of consanguinity between her parents. Her family history was insignificant for cancers, inherited bone marrow failure, or MDS. Her physical exam was unremarkable for any dysmorphic feature, telangiectasias, and she had a normal neurological examination. Her lab work showed normal immunoglobulins (9.92 g/L, reference range 5.40-13.60 g/L) and alpha-fetoprotein levels (<2 ng/mL, reference range 1-4 ng/mL).

| Initial bone marrow assessment
Bone marrow aspirate showed active erythropoiesis with megaloblastic changes and dysplastic nucleus. Granulopoiesis was reduced, leftshifted, and dysplastic. Megakaryocytes were reduced and dysplastic. She has a 10/10 matched sibling, but due to serious concern of underlying inherited BMF/MDS, we sent a whole-exome sequence (WES) analysis. Her WES came back +ve for SAMD9L heterozygous mutation of unknown significance (based on ACMG recommendation).
The variant was c.1949A > G p.(Glu650Gly) chr7:92763336. In the literature, the pathogenic variants in the SAMD9L gene lead to ataxia pancytopenia syndrome with a predisposition to AML, MDS, and bone marrow failure, which is present in this case. A segregation study for the family indicated that both her mother and sister have the same mutation but are asymptomatic with normal CBC. A magnetic resonance image (MRI) brain was performed even without neurological manifestations and showed mild prominence of the anterior (superior) vermis folia, suggesting mild atrophy with no other brain abnormalities

| CONCLUSION
This case illustrates the current established clinical feature of a form of SAMD9L genetic mutation, which can cause ataxia pancytopenia syndrome. This variant was not described previously but highlights that additional knowledge of this entity will allow easier detection in the future.

ACKNOWLEDGMENTS
Writer would like to thank all team members who had been involved in treating this young girl during difficult time of COVID-19 pandemic.

CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHICS STATEMENT
This manuscript was approved by our institutional ethics board.
Informed consent was taken from the patient's legal guardian.