Donor-type bone marrow aplasia following hematopoietic stem cell transplantation in a child with a novel SAMD9L variant.

Pathogenic variants in the genes SAMD9 (sterile a-motif domain containing protein - 9) and SAMD9L (SAMD9-like) cause bone marrow failure with characteristic syndromic features. We report a case of a previously healthy, 3-year-old boy with no dysmorphology, who presented with severe aplastic anemia and a novel variant in the SAMD9L gene. His father, elder brother and sister who harbored the same variant were completely healthy. In the absence of a matched unrelated donor, he underwent a stem cell transplant from his sister, a 10/10 match. Almost 2 years later he developed donor type aplasia and succumbed to an invasive fungal infection after a failed haplograft from his mother. This case highlights the pathogenicity of this previously undescribed germline variation of uncertain significance in the SAMD9L gene and the value of comprehensive genetic testing for inherited bone marrow failures even in the absence of a positive family history or characteristic congenital abnormalities.

Assessing Long-Term Neurologic Outcomes in SAMD9L-Related Ataxia-Pancytopenia Syndrome.

BACKGROUND: Most published reports on SAMD9L-related ataxia-pancytopenia syndrome (ATXPC) have emphasized the hematologic findings. Fewer details are known about the progression of neurologic manifestations and methods for monitoring them. CASES: We present six individuals from two families transmitting a heterozygous variant in SAMD9L, exhibiting clinical variations in their hematologic and neurologic findings. Serial motor function testing was used to monitor motor proficiency over a 2 to 3 year period in the proband and his father from Family 1. CONCLUSIONS: Our case series focuses on the neurologic progression in patients with heterozygous variants in SAMD9L. Patients with ATXPC should be followed to evaluate a wide range of neurologic manifestations. Serial motor function testing using a standardized method is helpful to track changes in balance and coordination in children and adults with ATXPC and could aid in a future extended natural history study.

Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome.

Due to the proliferation of genetic testing, pathogenic germline variants predisposing to hereditary hematological malignancy syndrome (HHMS) have been identified in an increasing number of genes. Consequently, the field of HHMS is gaining recognition among clinicians and scientists worldwide. Patients with germline genetic abnormalities often have poor outcomes and are candidates for allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT using blood from a related donor should be carefully considered because of the risk that the patient may inherit a pathogenic variant. At present, we now face the challenge of incorporating these advances into clinical practice for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and optimizing the management and surveillance of patients and asymptomatic carriers, with the limitation that evidence-based guidelines are often inadequate. The 2016 revision of the WHO classification added a new section on myeloid malignant neoplasms, including MDS and AML with germline predisposition. The main syndromes can be classified into three groups. Those without pre-existing disease or organ dysfunction; DDX41, TP53, CEBPA, those with pre-existing platelet disorders; ANKRD26, ETV6, RUNX1, and those with other organ dysfunctions; SAMD9/SAMD9L, GATA2, and inherited bone marrow failure syndromes. In this review, we will outline the role of the genes involved in HHMS in order to clarify our understanding of HHMS.

Cytogenetics in the management of bone marrow failure syndromes: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.

Germline Predisposition to Myeloid Neoplasms: Diagnostic Concepts and Classifications.

Molecular and sequencing advances have led to substantial breakthroughs in the discovery of new genes and inherited mutations associated with increased risk of developing myeloid malignancies. Many of the same germline mutated genes are also drivers of malignancy in sporadic cancer. Recognition of myeloid malignancy associated with germline mutations is essential for proper therapy, disease surveillance, informing related donor selection for hematopoietic stem cell transplantation, and genetic counseling of the patient and affected family members. Some germline mutations are associated with syndromic features that precede the development of malignancy; however, penetrance may be highly variable leading to masking of the syndromic phenotype and/or inherited etiology.

Integrated Analysis Identifies Upregulated SAMD9L as a Potential Biomarker Correlating with the Severity of Primary Sjögren's Syndrome.

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease with lymphocytic infiltration of the salivary and lachrymal glands, whose present disease-specific objective indicators are few and have shortcomings that should be addressed. An integrated analysis of sequencing data from different cohorts has the potential to unveil novel biomarkers in pSS. Methods: We identified 3 GEO datasets, including gene expression data from minor salivary gland (MSG) biopsy samples of 49 patients with pSS and 31 non-pSS and whole blood cells of 30 pSS patients and 30 healthy controls (HCs). Differentially expressed genes (DEGs) involved in pSS were identified from these datasets. Function Enrichment Analyses of common upregulated DEGs and PPI (protein-protein interaction) networks were performed. Furthermore, we have carried out further analysis of these DEGs to explore their potential clinical significance and diagnostic efficacy as a biomarker for pSS. Sterile Alpha Motif Domain Containing 9 Like (SAMD9L), one of the DEGs, has been identified as a promising candidate biomarker that correlates with the severity of pSS. This has been validated by analyzing local clinical samples from 30 pSS and non-pSS patients' MSG biopsies, as well as serum samples of 18 pSS and HC individuals. Finally, we performed correlation analysis to understand the relationship between SAMD9L and infiltrated immune cells. Results: We identified 10 common highly expressed DEGs in pSS of different tissues. These genes were mainly involved in virus infection-related pathways and inferno-related pathways. GEO data and our clinical data showed that SAMD9L increases with disease severity. Public and local cohorts showed that SAMD9L has high diagnostic performance (AUC=0.845-0.867) as a biomarker, and its AUC was comparable to the Focus score when combined with RF or SSA. Conclusion: Up-regulated SAMD9L may serve as a promising novel pSS diagnostic biomarker and have potential value for evaluating the severity of pSS.

Inherited bone marrow failure syndromes and germline predisposition to myeloid neoplasia: A practical approach for the pathologist.

The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.

How I diagnose myeloid neoplasms with germline predisposition.

OBJECTIVES: Pathologists play a crucial role in the initial diagnosis of germline predisposition to myeloid neoplasia and subsequent surveillance for disease progression. The diagnostic workup can be challenging, particularly if clinical history, laboratory testing, or genetic studies are incomplete or unavailable. METHODS: Through case-based examples, we illustrate common diagnostic challenges and pitfalls encountered during bone marrow examination of patients being evaluated for myeloid malignancy with potential germline predisposition to myeloid neoplasia. RESULTS: Lack of familial disease, the absence of syndromic manifestations, and late-onset hematologic malignancy do not exclude an underlying germline predisposition syndrome. Targeted myeloid sequencing panels can help identify potential germline alterations but may not detect large deletions or insertions, noncoding, or novel variants. Confirmation of the germline nature of an alteration detected in the peripheral blood or bone marrow ideally requires genetic testing using nonhematopoietic germline DNA to definitively distinguish between germline and somatic alterations. The ideal tissue source for germline testing is cultured skin fibroblasts. Certain germline predisposition syndromes can contain characteristic baseline bone marrow dysplastic-appearing features associated with cytopenias without constituting myelodysplastic syndrome. CONCLUSION: Recognizing germline predisposition to myeloid neoplasia is critical for proper disease management. This recognition is particularly important for patients who will undergo hematopoietic stem cell transplantation to screen potential related donors. Integration of the clinical history, bone marrow findings, cytogenetic studies, and specialized laboratory and molecular genetic testing is often essential for accurate diagnosis and subsequent disease monitoring.

Identification of sterile a-motif domain-containing 9-like as a potential biomarker in patients with cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is one of the most aggressive malignancies, accounting for approximately 75% of skin cancer-related fatalities annually. Sterile a-motif domain-containing 9-like (SAMD9L) has been found to regulate cell proliferation and suppress the neoplastic phenotype, but its specific role in SKCM remains unknown. To investigate the cancer-associated immunology of SKCM and the role of SAMD9L in tumor progression, we conducted an integrative bioinformatics analysis that revealed elevated expression levels of SAMD9L in SKCM. ROC curves and survival analyses confirmed the considerable diagnostic and prognostic abilities of SAMD9L. Moreover, a real-world cohort of 35 SKCM patients from the First Affiliated Hospital of Soochow University showed that higher expression levels of SAMD9L were associated with better prognosis. We performed validation experiments, including cell culture, generation of lentiviral-transfected SKCM cell lines, cell proliferation assay, and transwell assay, which demonstrated that down-regulation of SAMD9L significantly promoted proliferation and migration capacities of SKCM cells. Additionally, SAMD9L expression was found to be strongly linked to immune infiltration. Our results revealed a positive correlation between SAMD9L and XAF1 expression, suggesting that SAMD9L may serve as a prospective prognostic indicator of SKCM with co-expressed XAF1 gene. In summary, our findings indicate that SAMD9L may serve as a promising prognostic and therapeutic biomarker and play a critical role in tumor-immune interactions in SKCM.

Case report: De novo SAMD9L truncation causes neonatal-onset autoinflammatory syndrome which was successfully treated with hematopoietic stem cell transplantation.

During recent years, the identification of monogenic mutations that cause sterile inflammation has expanded the spectrum of autoinflammatory diseases, clinical disorders characterized by uncontrolled systemic and organ-specific inflammation that, in some cases, can mirror infectious conditions. Early studies support the concept of innate immune dysregulation with a predominance of myeloid effector cell dysregulation, particularly neutrophils and macrophages, in causing tissue inflammation. However, recent discoveries have shown a complex overlap of features of autoinflammation and/or immunodeficiency contributing to severe disease phenotypes. Here, we describe the first Argentine patient with a newly described frameshift mutation in SAMD9L c.2666delT/p.F889Sfs*2 presenting with a complex phenotypic overlap of CANDLE-like features and severe infection-induced cytopenia and immunodeficiency. The patient underwent a fully matched unrelated HSCT and has since been in inflammatory remission 5 years post-HSCT.

Viral host range factors antagonize pathogenic SAMD9 and SAMD9L variants.

SAMD9 and SAMD9L encode homologous interferon-induced genes that can inhibit cellular translation as well as proliferation and can restrict viral replication. Gain-of-function (GoF) variants in these ancient, yet rapidly evolving genes are associated with life-threatening disease in humans. Potentially driving population sequence diversity, several viruses have evolved host range factors that antagonize cell-intrinsic SAMD9/SAMD9L function. Here, to gain insights into the molecular regulation of SAMD9/SAMD9L activity and to explore the prospect of directly counteracting the activity of pathogenic variants, we examined whether dysregulated activity of pathogenic SAMD9/SAMD9L variants can be modulated by the poxviral host range factors M062, C7 and K1 in a co-expression system. We established that the virally encoded proteins retain interactions with select SAMD9/SAMD9L missense GoF variants. Furthermore, expression of M062, C7 and K1 could principally ameliorate the translation-inhibiting and growth-restrictive effect instigated by ectopically expressed SAMD9/SAMD9L GoF variants, yet with differences in potency. K1 displayed the greatest potency and almost completely restored cellular proliferation and translation in cells co-expressing SAMD9/SAMD9L GoF variants. However, neither of the viral proteins tested could antagonize a truncated SAMD9L variant associated with severe autoinflammation. Our study demonstrates that pathogenic SAMD9/SAMD9L missense variants can principally be targeted through molecular interactions, opening an opportunity for therapeutic modulation of their activity. Moreover, it provides novel insights into the complex intramolecular regulation of SAMD9/SAMD9L activity.

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

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.

The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia.

Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia.

Most cases of acquired aplastic anemia (AA) arise from autoimmune destruction of hematopoietic stem and progenitor cells. Human leukocyte antigen (HLA)-haploidentical nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus post-transplantation cyclophosphamide (PTCy) is increasingly applied to salvage AA using bone marrow as graft and anti-thymocyte globulin (ATG) in conditioning. Herein, we characterize a cohort of twelve AA patients clinically and molecularly, six who possessed other immunological disorders (including two also carrying germline SAMD9L mutations). Each patient with SAMD9L mutation also carried an AA-related rare BCORL1 variant or CTLA4 p.T17A GG genotype, respectively, and both presented short telomere lengths. Six of the ten patients analyzed harbored AA-risky HLA polymorphisms. All patients recovered upon non-HSCT (n = 4) or HSCT (n = 8) treatments. Six of the eight HSCT-treated patients were subjected to a modified PTCy-based regimen involving freshly prepared peripheral blood stem cells (PBSC) as graft and exclusion of ATG. All patients were engrafted between post-transplantation days +13 and +18 and quickly reverted to normal life, displaying a sustained complete hematologic response and an absence of graft-versus-host disease. These outcomes indicate most AA cases, including of the SAMD9L-inherited subtype, are immune-mediated and the modified PTCy-based regimen we present is efficient and safe for salvage.

Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy.

BACKGROUND: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. METHODS: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. RESULTS: Combined analysis of the mother's and daughter's duo-exome data and analysis of the mother's and her parents' trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. CONCLUSION: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult.

Evolution of Graves' Disease during Immune Reconstitution following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation in a Boy Carrying Germline SAMD9L and FLT3 Variants.

Graves' disease, characterized by hyperthyroidism resulting from loss of immune tolerance to thyroid autoantigens, may be attributable to both genetic and environmental factors. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a means to induce immunotolerance via an artificial immune environment. We present a male patient with severe aplastic anemia arising from a germline SAMD9L missense mutation who successfully underwent HSCT from his HLA-haploidentical SAMD9L non-mutated father together with nonmyeloablative conditioning and post-transplant cyclophosphamide at 8 years of age. He did not suffer graft-versus-host disease, but Graves' disease evolved 10 months post-transplant when cyclosporine was discontinued for one month. Reconstitution of peripheral lymphocyte subsets was found to be transiently downregulated shortly after Graves' disease onset but recovered upon antithyroid treatment. Our investigation revealed the presence of genetic factors associated with Graves' disease, including HLA-B*46:01 and HLA-DRB1*09:01 haplotypes carried by the asymptomatic donor and germline FLT3 c.2500C>T mutation carried by both the patient and the donor. Given his current euthyroid state with normal hematopoiesis, the patient has returned to normal school life. This rare event of Graves' disease in a young boy arising from special HSCT circumstances indicates that both the genetic background and the HSCT environment can prompt the evolution of Graves' disease.

Discovery of MIRAGE syndrome.

Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.

Up-regulated SAMD9L modulated by TLR2 and HIF-1α as a promising biomarker in tuberculosis.

The aim of this study was to identify potential biomarkers of TB in blood and determine their function in Mtb-infected macrophages. First of all, WGCNA was used to analyse 9451 genes with significant changes in TB patients' whole blood. The 220 interferon-γ-related genes were identified, and then 30 key genes were screened using Cytoscape. Then, the AUC values of key genes were calculated to further narrow the gene range. Finally, we identified 9 genes from GSE19444. ROC analysis showed that SAMD9L, among 9 genes, had a high diagnostic value (AUC = 0.925) and a differential diagnostic value (AUC>0.865). To further narrow down the range of DEGs, the top 10 hub-connecting genes were screened from monocytes (GSE19443). Finally, we obtained 4 genes (SAMD9L, GBP1, GBP5 and STAT1) by intersections of genes from monocytes and whole blood. Among them, it was found that the function of SAMD9L was unknown after data review, so this paper studied this gene. Our results showed that SAMD9L is up-regulated and suppresses cell necrosis, and might be regulated by TLR2 and HIF-1α during Mtb infection. In addition, miR-181b-5p is significantly up-regulated in the peripheral blood plasma of tuberculosis patients, which has a high diagnostic value (AUC = 0.969).

New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).

Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z max = 3.43; θ = 0.00; P < 3.53 × 10-5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions.