SAMD9L-Related Spectrum and Myeloid Neoplasm Risk

Genetic MONDO:1060111 Pathograph 41 Show in embeddings browser hereditary neoplastic syndrome

Autosomal dominant multisystem disorder caused by heterozygous germline gain-of-function variants in SAMD9L, an interferon-inducible negative regulator of cell proliferation on 7q21. The hyperactive protein represses global protein translation and restricts hematopoietic progenitor growth, producing cytopenias in a hypocellular marrow that usually present in infancy or early childhood, B- and NK-cell deficiency, and a predisposition to marrow failure, myelodysplasia and myeloid leukemia. A defining feature is frequent somatic genetic rescue in hematopoiesis. Clones that lose the mutant allele by monosomy 7 escape the growth block but carry myeloid-neoplasm risk (maladaptive rescue; monosomy 7 can be transient in young children), whereas clones with copy-neutral UPD7q or an in-cis somatic SAMD9L inactivating variant restore hematopoiesis (adaptive rescue). Neurologic disease (slowly progressive cerebellar ataxia, sensorimotor axonal neuropathy, white matter change) usually appears later, in adolescence or adulthood, and is not corrected by hematopoietic rescue or transplantation. ClinGen lumps ataxia-pancytopenia syndrome, monosomy 7 myelodysplasia and leukemia syndrome 1 and spinocerebellar ataxia 49 into this entity; GeneReviews additionally includes the truncating-variant SAMD9L-associated autoinflammatory subtype (SAAD). The paralogous SAMD9 disorder (MIRAGE syndrome and SAMD9-related myeloid predisposition) is a separate disease and is not covered here.

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1
Inheritance
10
Pathophys.
21
Phenotypes
3
Gaps
41
Pathograph
1
Genes
9
Medical Actions
4
Subtypes
1
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous germline SAMD9L variants, often de novo, transmitted as an autosomal dominant trait with marked intrafamilial variability. Apparent non-penetrance is frequent and is often explained by protective somatic rescue in hematopoiesis. Somatic loss of the mutant allele in blood can mask the germline variant, so parental testing should use non-hematopoietic DNA.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (4 references)
PMID:28570036 SUPPORT Other
"SAMD9L-related syndrome is an autosomal dominant disorder often caused by a de novo germline pathogenic variant."
GeneReviews statement of inheritance and de novo frequency.
PMID:28570036 SUPPORT Other
"reduced penetrance (often resulting from a "protective" second genetic event)"
GeneReviews attributes reduced penetrance to protective somatic events.
PMID:29217778 SUPPORT Human Clinical
"Incomplete penetrance was noted in 30% (3/10) of mutation carriers."
Quantifies non-penetrance in four familial MDS pedigrees.
+ 1 more reference
◆

Subtypes

4
Ataxia-pancytopenia syndrome MONDO:0008038
SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee.
The originally described familial presentation (OMIM 159550): cerebellar ataxia with variable cytopenias and predisposition to marrow failure and myeloid leukemia, sometimes with monosomy 7. Curated here as a presentation of the SAMD9L spectrum, following the ClinGen lumping, rather than as a separate disease.
Show evidence (2 references)
PMID:27259050 SUPPORT Human Clinical
"Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7."
Defines the ATXPC presentation in the gene-discovery report.
CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z SUPPORT Other
"the following disease entities have been lumped into one disease entity: ataxia-pancytopenia syndrome (OMIM:159550), monosomy 7 myelodysplasia and leukemia syndrome 1 (OMIM:252270), and spinocerebellar ataxia 49 (OMIM:619806)."
ClinGen CAYA Cancer Predisposition GCEP lumping decision placing ATXPC inside MONDO:1060111.
Monosomy 7 myelodysplasia and leukemia syndrome 1 MONDO:0009646
SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee.
Familial or sporadic childhood myelodysplasia with loss of chromosome 7/7q and hypocellular marrow, without neurologic or dysmorphic features at the time of report. Median age at diagnosis in the founding series was 2.1 years. Shares the germline SAMD9L gain-of-function mechanism and the somatic-rescue architecture of the other presentations.
Show evidence (2 references)
PMID:29217778 SUPPORT Human Clinical
"Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease."
Establishes isolated MDS with monosomy 7 as a presentation of germline SAMD9L disease.
PMID:30046003 SUPPORT Human Clinical
"we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270)"
Ties the OMIM 252270 familial monosomy 7 phenotype to germline SAMD9L variants (4 of 5 families).
Spinocerebellar ataxia 49 MONDO:0030805
SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee.
Neurologic-only presentation described in one five-generation Menorcan family carrying SAMD9L p.Ser626Leu: ataxia, gaze-evoked nystagmus, dysarthria, sensory axonal polyneuropathy, pyramidal signs, cerebellar atrophy and cerebral demyelination, with onset from 12 to 60 years. The report found decreased SAMD9L protein in patient fibroblasts, so whether this allele acts by the gain-of-function mechanism of the hematologic presentations is not settled (see discussions).
Show evidence (1 reference)
PMID:35310830 SUPPORT Human Clinical
"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"
Linkage-supported SAMD9L variant in the SCA49 family.
SAMD9L-associated autoinflammatory disease MONDO:0850066
SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee.
Severe neonatal- or infantile-onset autoinflammatory presentation caused by de novo frameshift variants that truncate SAMD9L C-terminal to its NOD-like region, removing autoregulatory domains while preserving the translational-repressor activity. Features include panniculitis with lipoatrophy, interstitial lung disease, basal ganglia calcification, cytopenias and B-cell deficiency. Included as a subtype because GeneReviews treats it as a subtype of the SAMD9L-related syndrome; ClinGen's lumping of MONDO:1060111 does not list it, and MONDO files it under autoinflammatory syndrome rather than under this term.
Show evidence (2 references)
PMID:28570036 SUPPORT Other
"SAMD9L-associated autoinflammatory subtype (SAAD) is a severe autoinflammatory phenotype with infantile or neonatal onset caused by pathogenic SAMD9L variants that truncate the autoregulatory domain but preserve the protein's enzymatic function."
GeneReviews places SAAD inside the SAMD9L-related syndrome as a subtype and states its variant class.
PMID:31874111 SUPPORT Human Clinical
"Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift..."
Original SAAD series of six patients with de novo SAMD9L frameshift variants.
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Discussions and Knowledge Gaps

3
Do germline loss-of-function SAMD9L alleles in adult-onset myeloid neoplasms belong to this disease?
CONTROVERSY adult_loss_of_function_arm
Attached to
genetic#SAMD9L
ClinGen's curation of MONDO:1060111 states that mechanism is gain of function for childhood onset and loss of function for adult onset, citing Nagata et al. 2018 (PMID:30322869). The pathograph here models only the gain-of-function chain. A loss-of-function allele would predispose by a different route (reduced tumor suppressor dosage, as in the Samd9l knockout mouse), with no growth restriction and no selection for rescue, and may be better modelled separately. The Nagata abstract is not available in the reference cache, so the adult arm is not curated as a claim.
Show evidence (1 reference)
CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z SUPPORT Other
"The mechanism of pathogenicity is reported to be gain of function for onset in childhood, loss of function for onset in adulthood (PMID: 30322869)."
ClinGen statement of the two mechanisms.
How do germline SAMD9L variants cause cerebellar and peripheral neurodegeneration, and does the SCA49 allele act by gain or loss of function?
KNOWLEDGE GAP neurodegeneration_mechanism
Attached to
pathophysiology#Cerebellar and Peripheral Neurodegeneration
The hematologic mechanism (translational repression and growth restriction relieved by somatic rescue) does not explain neurologic disease, which persists after hematopoietic rescue and transplantation. The SCA49 study reports decreased SAMD9L protein and mitochondrial perturbation in fibroblasts, which is not obviously a gain-of-function signature, while the ATXPC missense Arg986Cys is gain-of-function in translation assays. Whether one mechanism covers both, and whether neurons are sensitive to the same translation block, is not established.
In infants with SAMD9L disease and monosomy 7, when should surveillance give way to HSCT?
OPEN QUESTION monosomy7_transplant_timing
Attached to
treatments#Allogeneic Hematopoietic Stem Cell Transplantation
Monosomy 7 regresses spontaneously in some young children, but delay risks severe infection and progression; the cited series is small and there are no evidence-based surveillance protocols.
Show evidence (1 reference)
PMID:39475954 SUPPORT Human Clinical
"Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes."
Authors identify transplant timing as unresolved.
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Pathophysiology

10
SAMD9L Gain-of-Function Variant
Heterozygous germline missense variants, or C-terminal truncating frameshifts in SAAD, render SAMD9L constitutively more active as an antiproliferative factor. The germline variant is present in every cell, including non-hematopoietic tissue.
SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee.
translation repressor activity GO:0030371 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased translation repressor activity (GO:0030371). GO:0030371 is a molecular function from the Gene Ontology.
Downstream
Global Translational Repression Mutant SAMD9L, both truncating and ATXPC missense alleles, represses protein synthesis more strongly than wild type at the same expression level.
Cerebellar and Peripheral Neurodegeneration The neurologic disease follows from the constitutional variant in neural tissue rather than from the hematopoietic lesion: it persists when blood has been rescued and progresses after transplantation. The intermediate mechanism in neurons is unresolved.
Show evidence (2 references)
PMID:34417303 SUPPORT In Vitro
"Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection."
Describes SAMD9L as a translational repressor whose activity the truncating variants leave unchecked; grounds the molecular-function binding. Whether the repression is enzymatic is not stated in the cached sources.
PMID:28202457 SUPPORT In Vitro
"Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein."
Functional evidence that the patient alleles are gain-of-function.
Interferon-Driven SAMD9L Induction
SAMD9L is an interferon-stimulated gene. Interferon signalling during infection raises expression of the mutant protein in hematopoietic progenitors and lymphocytes, which is proposed to explain why cytopenic and myelodysplastic episodes follow infections.
response to type I interferon GO:0034340 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to type I interferon (GO:0034340). GO:0034340 is a biological process from the Gene Ontology. cellular response to type II interferon GO:0071346 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cellular response to type II interferon (GO:0071346). GO:0071346 is a biological process from the Gene Ontology.
Downstream
Global Translational Repression Interferon raises expression of the truncated SAAD protein, which then suppresses global protein synthesis.
Show evidence (3 references)
PMID:28202457 SUPPORT In Vitro
"Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression."
Interferon-alpha and -gamma induce SAMD9L in B and NK cells.
PMID:28202457 SUPPORT Human Clinical
"3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency."
Clinical observation that MDS followed infections in carriers.
PMID:28202457 SUPPORT Human Clinical
"The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis."
The authors' interpretation; supports interferon-driven SAMD9L activity as a modifier of hematopoiesis, stated as a suggestion.
Global Translational Repression
Hyperactive SAMD9L inhibits translational elongation and globally suppresses protein synthesis cell autonomously, in proportion to its expression level.
negative regulation of translation GO:0017148 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of translation (GO:0017148). GO:0017148 is a biological process from the Gene Ontology.
Downstream
Hematopoietic Progenitor Growth Restriction and Death The translation block is proposed to account for the lineage-dominant failure of hematopoietic progenitors and lymphocytes; the authors frame the lineage specificity as a sensitivity difference.
Autoinflammation In SAAD, the unchecked translational repressor is proposed to underlie the autoinflammatory disease; how translation arrest produces inflammation is not established.
Show evidence (1 reference)
PMID:33724365 SUPPORT In Vitro
"This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation."
Mechanism of the translational block for a truncating SAMD9L allele.
Hematopoietic Progenitor Growth Restriction and Death
Mutant SAMD9L suppresses proliferation of hematopoietic stem and progenitor cells and induces death of CD34+ cells, producing a hypocellular marrow with multilineage cytopenia. This growth block is also the selective pressure that favours any clone which loses or silences the mutant allele.
CD34+ hematopoietic stem and progenitor cell CL:0000837 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD34+ hematopoietic stem and progenitor cell, annotated with hematopoietic multipotent progenitor cell (CL:0000837). CL:0000837 is a cell type from the Cell Ontology.
negative regulation of cell population proliferation GO:0008285 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of cell population proliferation (GO:0008285). GO:0008285 is a biological process from the Gene Ontology.
Downstream
Pancytopenia
Thrombocytopenia
Neutropenia
Bone Marrow Hypocellularity
Maladaptive Somatic Rescue by Monosomy 7 Cells that lose the chromosome 7 carrying the mutant allele escape the growth block and are positively selected.
Adaptive Somatic Rescue by UPD7q or In-cis SAMD9L Inactivation The same selective pressure favours clones that remove the mutant allele without losing the rest of chromosome 7.
Show evidence (2 references)
PMID:34621053 SUPPORT In Vitro
"Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death."
Functional testing of patient alleles (pooled SAMD9 and SAMD9L) in a cell line and in CD34+ progenitors.
PMID:33731850 SUPPORT In Vitro
"expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells."
Lentiviral expression of wild-type and mutant SAMD9/SAMD9L in primary mouse and human HSPCs; results are reported jointly for the two genes.
Maladaptive Somatic Rescue by Monosomy 7
Loss of chromosome 7 or 7q removes the mutant SAMD9L allele and relieves the growth block, but leaves the clone haploinsufficient for chromosome 7 genes including wild-type SAMD9L, SAMD9 and other 7q myeloid tumor suppressors. In young children the monosomy 7 clone can regress spontaneously (transient monosomy 7). Monosomy 7 has no HPO term, so it is modelled as this node rather than as a phenotype.
Animal models
Samd9l-deficient mouse Mouse partially recapitulates Reproduces the myeloid consequence of SAMD9L haploinsufficiency that a monosomy 7 clone carries.
Downstream
Myelodysplasia
Clonal Evolution with Cooperating Somatic Mutations Monosomy 7 clones can acquire cooperating driver mutations and progress.
Show evidence (4 references)
PMID:39475954 SUPPORT Human Clinical
"Somatic genetic rescue occurs in two-third of patients or more and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to myelodysplastic syndrome (MDS)/leukemia"
Registry-level statement (pooled SAMD9/SAMD9L) of rescue frequency and the two fates of monosomy 7.
PMID:34621053 SUPPORT Human Clinical
"we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations)"
Pediatric MDS cohort (n = 669) quantification of rescue; pooled SAMD9 and SAMD9L.
PMID:29146883 SUPPORT Human Clinical
"SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7"
Independent inherited marrow-failure cohort (germline DNA from skin fibroblasts); SAMD9 and SAMD9L reported together.
+ 1 more reference
Adaptive Somatic Rescue by UPD7q or In-cis SAMD9L Inactivation
Copy-neutral loss of heterozygosity of 7q (uniparental disomy) that retains only the wild-type allele, or an acquired truncating SAMD9L variant in cis with the germline variant, restores hematopoiesis without loss of chromosome 7. Revertant clones are associated with hematologic remission and milder disease, and can make a carrier appear unaffected. This is a protective terminal branch: it has no phenotype target because its consequence is the absence of cytopenia.
Show evidence (3 references)
PMID:28202457 SUPPORT Human Clinical
"Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations."
Both adaptive mechanisms in SAMD9L carriers, with resolved infantile cytopenias. The missing space in "cisSAMD9L" is in the PubMed record.
PMID:39475954 SUPPORT Human Clinical
"adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission"
Registry-level statement that adaptive clones associate with remission.
PMID:37584291 SUPPORT Human Clinical
"Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission."
In-cis somatic SAMD9L subclones in infants with monosomy 7; two of the five did not remit, so a rescue variant alone does not predict recovery. The image is the paper's longitudinal course for one patient (somatic in-cis variant fractions, monosomy 7 clone and neutrophil count).
Artifact: image-1.png
image-1.png
Clonal Evolution with Cooperating Somatic Mutations
Monosomy 7 clones accumulate cooperating somatic driver mutations (RUNX1 and EZH2 among those reported) and progress from refractory cytopenia to MDS with excess blasts or AML.
Downstream
Myelodysplasia
Acute Myeloid Leukemia
Show evidence (2 references)
PMID:37584291 SUPPORT Human Clinical
"Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB)."
Acquisition of cooperating mutations and progression under surveillance.
PMID:29217778 SUPPORT Human Clinical
"Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2)."
Divergent clonal outcomes in familial SAMD9L MDS.
B and NK Lymphocyte Deficiency
B and NK cells are disproportionately depleted, consistent with their high SAMD9L inducibility and with enrichment of revertant clones in these lineages. The resulting humoral and innate defect predisposes to infections. Whether those infections feed back on SAMD9L through interferon induction is plausible but not shown, so no edge is drawn for it.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
Downstream
Decreased Total B Cell Count
Reduced Natural Killer Cell Count
Recurrent Infections
Hypogammaglobulinemia
Show evidence (2 references)
PMID:28570036 SUPPORT Other
"Immunodeficiency most often consists of B and NK cell deficiencies."
GeneReviews characterization of the immunodeficiency.
PMID:28202457 SUPPORT Human Clinical
"Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells."
Revertant somatic variants are enriched in B and NK cells, consistent with strong selection against the mutant allele in these lineages.
Cerebellar and Peripheral Neurodegeneration
Slowly progressive cerebellar degeneration with Purkinje-cell involvement, sensorimotor axonal neuropathy and cerebral white matter change. Neurologic onset is typically in adolescence or adulthood, later than the hematologic disease, and imaging changes can precede symptoms. In the SCA49 family SAMD9L localized to mitochondria and patient fibroblasts showed mitochondrial perturbation; in one SAAD infant autopsy showed selective Purkinje-cell loss. How SAMD9L variants damage neurons is unresolved.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology.
Downstream
Progressive Cerebellar Ataxia
Cerebellar Atrophy
Sensorimotor Neuropathy
Cerebral White Matter Abnormalities
Gaze-Evoked Nystagmus
Dysautonomia
Dysarthria
Show evidence (3 references)
PMID:28570036 SUPPORT Other
"The neurologic manifestations typically have later onset – during adolescence or less often adulthood – and include slowly progressive cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and paracentral retinal dysfunction."
GeneReviews summary of the neurologic arm and its onset.
PMID:33724365 SUPPORT Human Clinical
"Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells."
Neuropathologic Purkinje-cell loss in a SAAD infant (single case).
PMID:35310830 SUPPORT In Vitro
"We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations."
Candidate mitochondrial mechanism, from the SCA49 family only.
Autoinflammation
In the SAAD subtype, neonatal- or infantile-onset systemic inflammation with an interferon-response gene signature that differs from the canonical interferonopathies, presenting as panniculitis, lipoatrophy, interstitial lung disease and basal ganglia calcification.
Downstream
Panniculitis
Lipoatrophy
Interstitial Lung Disease
Basal Ganglia Calcification
Show evidence (1 reference)
PMID:31874111 SUPPORT Human Clinical
"Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS."
Characterizes the inflammatory signature of SAAD.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SAMD9L-Related Spectrum and Myeloid Neoplasm Risk Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

21
Blood 9
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876), qualified as infantile onset. HP:0001876 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Cytopenias affecting all hematopoietic lineages arise in a typically hypocellular marrow, range from mild to severe, and most often present in infancy or early childhood."
GeneReviews description of the cytopenias and their onset.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29217778 SUPPORT Human Clinical
"All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts."
Thrombocytopenia as the universal presenting cytopenia (n = 7).
Neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37584291 SUPPORT Human Clinical
"At diagnosis, all patients had moderate to severe neutropenia and three children (P1, P2, P3) required platelet transfusions."
Neutropenia at diagnosis in a selected cohort of seven children.
Bone Marrow Hypocellularity HP:0005528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone marrow hypocellularity (HP:0005528). HP:0005528 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29217778 SUPPORT Human Clinical
"All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts."
Hypocellular marrow at presentation in the familial MDS series.
Myelodysplasia HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelodysplasia (HP:0002863), qualified as childhood onset. HP:0002863 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (3 references)
PMID:34621053 SUPPORT Human Clinical
"Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%"
MDS subtype and monosomy 7 frequency; pooled SAMD9 and SAMD9L.
PMID:34621053 SUPPORT Human Clinical
"In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8%"
Share of pediatric MDS explained by germline SAMD9/SAMD9L (pooled).
PMID:29217778 SUPPORT Human Clinical
"Their median age at diagnosis was 2.1 years (range, 1-42)."
Onset age of MDS with chromosome 7 loss in SAMD9L families.
Acute Myeloid Leukemia HP:0004808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute myeloid leukemia (HP:0004808). HP:0004808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Individuals have a predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7."
GeneReviews statement of myeloid leukemia predisposition.
Decreased Total B Cell Count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is B-cell deficiency, annotated with Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Immunodeficiency most often consists of B and NK cell deficiencies."
GeneReviews.
Reduced Natural Killer Cell Count Reduced total natural killer cell count HP:0040218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is NK-cell deficiency, annotated with Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Immunodeficiency most often consists of B and NK cell deficiencies."
GeneReviews.
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37584291 SUPPORT Human Clinical
"The most consistent findings of immunological impairment were hypogammaglobulinemia found in five patients (P1, P2, P5, P6, P7) and B- and natural killer (NK)-cell deficiency present in four (P2, P5, P6, P7)."
Hypogammaglobulinemia in a selected cohort of seven children.
Eye 1
Gaze-Evoked Nystagmus HP:0000640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gaze-evoked nystagmus (HP:0000640). HP:0000640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35310830 SUPPORT Human Clinical
"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."
Initial sign and onset range in SCA49.
Immune 2
Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28202457 SUPPORT Human Clinical
"3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency."
Infections associated with the immune deficiency in carriers.
Panniculitis HP:0012490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Panniculitis (HP:0012490), qualified as neonatal onset. HP:0012490 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:34417303 SUPPORT Human Clinical
"Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations"
Panniculitis in two SAAD children.
Musculoskeletal 2
Lipoatrophy HP:0100578 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lipoatrophy (HP:0100578). HP:0100578 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"This phenotype may include cytopenias, skin inflammation, lipoatrophy, early-onset interstitial lung disease, and basal ganglia calcifications."
GeneReviews SAAD feature list.
Basal Ganglia Calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135). HP:0002135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34417303 SUPPORT Human Clinical
"Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations"
Basal ganglia calcification in two SAAD children.
Nervous System 6
Progressive Cerebellar Ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Slowly progressive cerebellar ataxia, annotated with Progressive cerebellar ataxia (HP:0002073), qualified as juvenile onset. HP:0002073 is a phenotype from the Human Phenotype Ontology.
Onset: JUVENILE
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"The neurologic manifestations typically have later onset – during adolescence or less often adulthood – and include slowly progressive cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and paracentral retinal dysfunction."
GeneReviews description and onset of the ataxia.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Even before these manifestations are apparent, brain imaging may show cerebellar atrophy and periventricular and deep white matter abnormalities and/or cysts."
GeneReviews imaging findings, preceding symptoms.
Cerebral White Matter Abnormalities Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular and deep white matter abnormalities, annotated with Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Even before these manifestations are apparent, brain imaging may show cerebellar atrophy and periventricular and deep white matter abnormalities and/or cysts."
GeneReviews does not specify signal characteristics, so the general white matter morphology term is bound rather than a hyperintensity term.
Sensorimotor Neuropathy HP:0007141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorimotor axonal polyneuropathy, annotated with Sensorimotor neuropathy (HP:0007141). HP:0007141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"The neurologic manifestations typically have later onset – during adolescence or less often adulthood – and include slowly progressive cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and paracentral retinal dysfunction."
GeneReviews.
Dysautonomia Abnormal autonomic nervous system physiology HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysautonomia, annotated with Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"The neurologic manifestations typically have later onset – during adolescence or less often adulthood – and include slowly progressive cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and paracentral retinal dysfunction."
GeneReviews.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35310830 SUPPORT Human Clinical
"affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination"
Dysarthria in the SCA49 family.
PMID:28570036 SUPPORT Other
"referral for speech and language therapy, including evaluation for alternative communication methods, as clinically indicated for dysarthria"
GeneReviews management of dysarthria across the syndrome; a management statement, not a frequency.
Respiratory 1
Interstitial Lung Disease Abnormal pulmonary interstitial morphology HP:0006530 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial lung disease, annotated with Abnormal pulmonary interstitial morphology (HP:0006530). HP:0006530 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"This phenotype may include cytopenias, skin inflammation, lipoatrophy, early-onset interstitial lung disease, and basal ganglia calcifications."
GeneReviews SAAD feature list.
🧬

Genetic Associations

1
SAMD9L
Gene: SAMD9L hgnc:1349 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SAMD9L (hgnc:1349). hgnc:1349 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:28202457 SUPPORT Human Clinical
"Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q)"
Establishes germline gain-of-function SAMD9L variants as causal.
PMID:39475954 SUPPORT Human Clinical
"Most patients (>90%) carry germ line missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease carry frameshift-truncating variants that are also GoF."
Registry of 243 published SAMD9/SAMD9L patients; the missense fraction is pooled across both genes, the truncating-GoF statement is SAMD9L-specific.
CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z SUPPORT Other
"The mechanism of pathogenicity is reported to be gain of function for onset in childhood, loss of function for onset in adulthood (PMID: 30322869)."
ClinGen's statement of the age-dependent mechanism split; the adult loss-of-function arm is discussed separately.
💊

Medical Actions

9
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Considered for MDS, leukemia, severe immune deficiency or autoinflammatory manifestations. Timing is the central pediatric question, because monosomy 7 can regress spontaneously in young children but delay carries risk of infection and progression. Transplantation does not halt the neurologic disease.
Mechanism Target:
Hematopoietic Progenitor Growth Restriction and Death — Replaces the SAMD9L-mutant hematopoietic compartment.
Clonal Evolution with Cooperating Somatic Mutations — Eradicates monosomy 7 and malignant clones.
Autoinflammation — Replaces the hematopoietic source of inflammation in SAAD; supported by a single case.
Show evidence (3 references)
PMID:28570036 SUPPORT Other
"consider hematopoietic stem cell transplantation (HSCT) and/or chemotherapy for myelodysplasia, leukemia, severe immune deficiency, or autoinflammatory manifestations"
GeneReviews management recommendation.
PMID:37584291 SUPPORT Human Clinical
"However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression."
Risk of deferring transplant in SAMD9L infants with monosomy 7.
PMID:36969289 SUPPORT Human Clinical
"The patient underwent a fully matched unrelated HSCT and has since been in inflammatory remission 5 years post-HSCT."
Single SAAD case (p.F889Sfs*2) in sustained inflammatory remission after HSCT; a case report, not a response rate.
Hematologic and Genetic Surveillance
No established guideline exists. GeneReviews suggests hematology review and CBC every 6-12 months, baseline and annual marrow examination by shared decision, more frequent monitoring for new cytopenias or monosomy 7, and annual immunologic evaluation. In infants with monosomy 7, close genetic surveillance of clone size and acquired mutations is used to time HSCT.
Mechanism Target:
Maladaptive Somatic Rescue by Monosomy 7 — Tracks monosomy 7 clone size and regression.
Clonal Evolution with Cooperating Somatic Mutations — Detects acquisition of cooperating driver mutations.
Show evidence (2 references)
PMID:28570036 SUPPORT Other
"There are no established surveillance guidelines but suggested approaches include: clinical evaluation with a hematologist every six to 12 months depending on age and presence of cytopenias or monosomy 7; complete blood count with differential every six to 12 months; consider bone marrow..."
GeneReviews suggested surveillance.
PMID:37584291 SUPPORT Human Clinical
"surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT"
Surveillance-first approach in seven infants with monosomy 7.
Transfusion Support
Action: red cell and platelet transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is red cell and platelet transfusion, annotated with Blood Transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Platform: Other
Red cell and/or platelet transfusion for symptomatic cytopenias.
Target Phenotypes: Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Provide supportive care with red cell and/or platelet transfusions as needed"
GeneReviews supportive care.
Corticosteroids or JAK Inhibitors for Autoinflammation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest. JAK inhibitor NCIT:C172200 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses JAK inhibitor (NCIT:C172200). NCIT:C172200 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Considered for autoinflammatory (SAAD) manifestations; supported by expert recommendation, not by trial data.
Mechanism Target:
Autoinflammation — Suppresses the inflammatory arm in SAAD.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Consider corticosteroids or JAK inhibitors for autoinflammatory manifestations"
GeneReviews management recommendation.
Immunoglobulin Replacement
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Considered to reduce infections that may exacerbate disease.
Mechanism Target:
B and NK Lymphocyte Deficiency — Replaces deficient humoral immunity.
Target Phenotypes: Hypogammaglobulinemia HP:0004313 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"consider immunoglobulin replacement to reduce infections that may exacerbate disease"
GeneReviews management recommendation.
Riluzole Trial for Ataxia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: riluzole CHEBI:8863 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses riluzole (CHEBI:8863). CHEBI:8863 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A trial of riluzole may be considered for ataxia symptoms, alongside supportive rehabilitation; no SAMD9L-specific efficacy data are cited.
Target Phenotypes: Slowly progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Slowly progressive cerebellar ataxia, annotated with Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"consider a trial of riluzole to improve ataxia symptoms"
GeneReviews management suggestion.
Avoidance of Antiplatelet, Anticoagulant and Thrombolytic Agents in Severe Thrombocytopenia
NSAIDs, anticoagulants and thrombolytics are contraindicated when thrombocytopenia is severe, and otherwise used with caution because the cytopenias fluctuate. An expert precaution, not a trial result.
Target Phenotypes: Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if severe thrombocytopenia is present and otherwise should be used with caution given the fluctuating nature of the cytopenias"
GeneReviews agents/circumstances to avoid.
Avoidance of Alcohol and Sedating Medications
Alcohol and centrally acting sedating medications can worsen gait and coordination in individuals with ataxia. An expert precaution.
Target Phenotypes: Slowly progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Slowly progressive cerebellar ataxia, annotated with Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"avoid alcohol and centrally acting medications that cause sedation, which can increase problems with gait and coordination"
GeneReviews agents/circumstances to avoid.
Cascade Testing of At-Risk Relatives
Action: Genetic counseling and cascade testingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling and cascade testing, annotated with Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Testing for the familial variant identifies relatives who would benefit from hematologic surveillance. Because of somatic rescue, testing of relatives should use non-hematopoietic DNA when blood is negative.
Show evidence (1 reference)
PMID:28570036 SUPPORT Other
"Offer molecular genetic testing for the familial SAMD9L pathogenic variant to asymptomatic at-risk relatives to identify those who would benefit from hematologic surveillance and early treatment of severe cytopenias or myeloid malignancy."
GeneReviews recommendation for relatives.
🔬

Diagnosis

1
Germline SAMD9L testing on non-hematopoietic DNA
Diagnosis rests on a heterozygous germline SAMD9L gain-of-function variant. Because monosomy 7 or UPD7q can lower or erase the variant allele fraction in blood, marrow, buccal or saliva DNA, a negative or apparently somatic result in those tissues does not exclude the disease, and testing of a non-hematopoietic tissue may be needed.
Germline genetic testing of non-hematopoietic tissue NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28570036 SUPPORT Other
"Acquired monosomy 7 or uniparental disomy of 7q can reduce the variant allele frequency of a germline SAMD9L pathogenic variant in blood-, bone marrow-, buccal mucosa-, or saliva-derived DNA, leading to failure to identify the pathogenic variant or misclassification as somatic."
GeneReviews diagnostic caveat specific to this disease.
PMID:28570036 SUPPORT Other
"The diagnosis of SAMD9L-related syndrome is established in a proband with a heterozygous germline gain-of-function pathogenic variant in SAMD9L identified by molecular genetic testing."
GeneReviews diagnostic criterion.
🐁

Animal Models

1
Samd9l-deficient mouse
Heterozygous and homozygous Samd9l knockout mice develop myeloid disease resembling human -7/7q- disease. This is a loss-of-function model: it does not model the germline gain-of-function lesion, but models the consequence of losing one SAMD9L copy, which is part of what a monosomy 7 rescue clone carries.
Species
Mouse
Genotype
Samd9l+/- and Samd9l-/-
Publication
PMID:24029230
Pathograph links
Maladaptive Somatic Rescue by Monosomy 7 partially recapitulates fidelity: low Reproduces the myeloid consequence of SAMD9L haploinsufficiency that a monosomy 7 clone carries.
Limitations: Models loss of function, the opposite of the germline lesion; no gain-of-function background and no loss of the other chromosome 7 genes.
Show evidence (1 reference)
PMID:24029230 SUPPORT Model Organism
"We established SAMD9L-deficient mice and found that SAMD9L(+/-) mice as well as SAMD9L(-/-) mice develop myeloid diseases resembling human diseases associated with -7/7q-."
Samd9l loss in mice produces -7/7q-like myeloid disease.
{ }

Source YAML

click to show 
name: SAMD9L-Related Spectrum and Myeloid Neoplasm Risk
creation_date: "2026-10-13T18:58:31Z"
description: >-
  Autosomal dominant multisystem disorder caused by heterozygous germline
  gain-of-function variants in SAMD9L, an interferon-inducible negative
  regulator of cell proliferation on 7q21. The hyperactive protein represses
  global protein translation and restricts hematopoietic progenitor growth,
  producing cytopenias in a hypocellular marrow that usually present in infancy
  or early childhood, B- and NK-cell deficiency, and a predisposition to marrow
  failure, myelodysplasia and myeloid leukemia. A defining feature is frequent
  somatic genetic rescue in hematopoiesis. Clones that lose the mutant allele by
  monosomy 7 escape the growth block but carry myeloid-neoplasm risk (maladaptive
  rescue; monosomy 7 can be transient in young children), whereas clones with
  copy-neutral UPD7q or an in-cis somatic SAMD9L inactivating variant restore
  hematopoiesis (adaptive rescue). Neurologic disease (slowly progressive
  cerebellar ataxia, sensorimotor axonal neuropathy, white matter change)
  usually appears later, in adolescence or adulthood, and is not corrected by
  hematopoietic rescue or transplantation. ClinGen lumps ataxia-pancytopenia
  syndrome, monosomy 7 myelodysplasia and leukemia syndrome 1 and
  spinocerebellar ataxia 49 into this entity; GeneReviews additionally includes
  the truncating-variant SAMD9L-associated autoinflammatory subtype (SAAD). The
  paralogous SAMD9 disorder (MIRAGE syndrome and SAMD9-related myeloid
  predisposition) is a separate disease and is not covered here.
category: Genetic
parents:
- hereditary neoplastic syndrome
synonyms:
- SAMD9L-related syndrome
- SAMD9L syndrome
disease_term:
  preferred_term: SAMD9L-related spectrum and myeloid neoplasm risk
  term:
    id: MONDO:1060111
    label: SAMD9L-related spectrum and myeloid neoplasm risk
references:
- reference: PMID:28570036
  title: SAMD9L-Related Syndrome.
  tags:
  - GeneReviews
has_subtypes:
- name: ATXPC
  display_name: Ataxia-pancytopenia syndrome
  subtype_term:
    preferred_term: ataxia-pancytopenia syndrome
    term:
      id: MONDO:0008038
      label: ataxia-pancytopenia syndrome
  description: >-
    The originally described familial presentation (OMIM 159550): cerebellar
    ataxia with variable cytopenias and predisposition to marrow failure and
    myeloid leukemia, sometimes with monosomy 7. Curated here as a presentation
    of the SAMD9L spectrum, following the ClinGen lumping, rather than as a
    separate disease.
  genes:
  - preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  evidence:
  - reference: PMID:27259050
    reference_title: Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia,
      variable hematologic cytopenias, and predisposition to marrow failure and
      myeloid leukemia, sometimes associated with monosomy 7.
    explanation: Defines the ATXPC presentation in the gene-discovery report.
  - reference: CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z
    reference_title: SAMD9L / SAMD9L-related spectrum and myeloid neoplasm risk (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the following disease entities have been lumped into one disease entity:
      ataxia-pancytopenia syndrome (OMIM:159550), monosomy 7 myelodysplasia and
      leukemia syndrome 1 (OMIM:252270), and spinocerebellar ataxia 49
      (OMIM:619806).
    explanation: >-
      ClinGen CAYA Cancer Predisposition GCEP lumping decision placing ATXPC
      inside MONDO:1060111.
- name: M7MLS1
  display_name: Monosomy 7 myelodysplasia and leukemia syndrome 1
  subtype_term:
    preferred_term: monosomy 7 myelodysplasia and leukemia syndrome 1
    term:
      id: MONDO:0009646
      label: monosomy 7 myelodysplasia and leukemia syndrome 1
  description: >-
    Familial or sporadic childhood myelodysplasia with loss of chromosome 7/7q
    and hypocellular marrow, without neurologic or dysmorphic features at the
    time of report. Median age at diagnosis in the founding series was 2.1
    years. Shares the germline SAMD9L gain-of-function mechanism and the
    somatic-rescue architecture of the other presentations.
  genes:
  - preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  evidence:
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features or neurological symptoms were absent in our patients,
      pointing to the notion that myelodysplasia with monosomy 7 can be a sole
      manifestation of SAMD9L disease.
    explanation: >-
      Establishes isolated MDS with monosomy 7 as a presentation of germline
      SAMD9L disease.
  - reference: PMID:30046003
    reference_title: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe 16 siblings, the majority of which were phenotypically normal,
      from 5 families diagnosed with myelodysplasia and leukemia syndrome with
      monosomy 7 (MLSM7; OMIM 252270)
    explanation: >-
      Ties the OMIM 252270 familial monosomy 7 phenotype to germline SAMD9L
      variants (4 of 5 families).
- name: SCA49
  display_name: Spinocerebellar ataxia 49
  subtype_term:
    preferred_term: spinocerebellar ataxia 49
    term:
      id: MONDO:0030805
      label: spinocerebellar ataxia 49
  description: >-
    Neurologic-only presentation described in one five-generation Menorcan
    family carrying SAMD9L p.Ser626Leu: ataxia, gaze-evoked nystagmus,
    dysarthria, sensory axonal polyneuropathy, pyramidal signs, cerebellar
    atrophy and cerebral demyelination, with onset from 12 to 60 years. The
    report found decreased SAMD9L protein in patient fibroblasts, so whether
    this allele acts by the gain-of-function mechanism of the hematologic
    presentations is not settled (see discussions).
  genes:
  - preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  evidence:
  - reference: PMID:35310830
    reference_title: New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: Linkage-supported SAMD9L variant in the SCA49 family.
- name: SAAD
  display_name: SAMD9L-associated autoinflammatory disease
  subtype_term:
    preferred_term: SAMD9L-associated autoinflammatory syndrome
    term:
      id: MONDO:0850066
      label: SAMD9L-associated autoinflammatory syndrome
  description: >-
    Severe neonatal- or infantile-onset autoinflammatory presentation caused by
    de novo frameshift variants that truncate SAMD9L C-terminal to its
    NOD-like region, removing autoregulatory domains while preserving the
    translational-repressor activity. Features include panniculitis with
    lipoatrophy, interstitial lung disease, basal ganglia calcification,
    cytopenias and B-cell deficiency. Included as a subtype because GeneReviews
    treats it as a subtype of the SAMD9L-related syndrome; ClinGen's lumping of
    MONDO:1060111 does not list it, and MONDO files it under autoinflammatory
    syndrome rather than under this term.
  genes:
  - preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SAMD9L-associated autoinflammatory subtype (SAAD) is a severe
      autoinflammatory phenotype with infantile or neonatal onset caused by
      pathogenic SAMD9L variants that truncate the autoregulatory domain but
      preserve the protein's enzymatic function.
    explanation: >-
      GeneReviews places SAAD inside the SAMD9L-related syndrome as a subtype
      and states its variant class.
  - reference: PMID:31874111
    reference_title: Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with panniculitis and progressive cytopenias, 2 patients
      were compound heterozygous for potentially novel LRBA mutations, 4
      patients harbored potentially novel splice variants in IKBKG (which
      encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo
      frameshift mutations in SAMD9L.
    explanation: >-
      Original SAAD series of six patients with de novo SAMD9L frameshift
      variants.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Heterozygous germline SAMD9L variants, often de novo, transmitted as an
    autosomal dominant trait with marked intrafamilial variability. Apparent
    non-penetrance is frequent and is often explained by protective somatic
    rescue in hematopoiesis. Somatic loss of the mutant allele in blood can mask
    the germline variant, so parental testing should use non-hematopoietic DNA.
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SAMD9L-related syndrome is an autosomal dominant disorder often caused by
      a de novo germline pathogenic variant.
    explanation: GeneReviews statement of inheritance and de novo frequency.
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      reduced penetrance (often resulting from a "protective" second genetic
      event)
    explanation: >-
      GeneReviews attributes reduced penetrance to protective somatic events.
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Incomplete penetrance was noted in 30% (3/10) of mutation carriers.
    explanation: Quantifies non-penetrance in four familial MDS pedigrees.
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with SAMD9L-related syndrome has a 50% chance
      of inheriting the SAMD9L pathogenic variant.
    explanation: GeneReviews statement of the transmission risk to offspring.
genetic:
- name: SAMD9L
  notes: >-
    Most pathogenic alleles are germline missense gain-of-function variants
    clustering in the middle region of the protein; the SAAD subtype carries de
    novo frameshift variants that truncate the C-terminus and are also
    gain-of-function. ClinGen additionally notes reported germline
    loss-of-function SAMD9L alleles in adult-onset myeloid neoplasms (Nagata et
    al. 2018, PMID:30322869, whose abstract is not cached here); that
    mechanism is opposite to the pediatric one and is recorded as a
    discussion rather than as part of this entry's causal chain.
  gene_term:
    preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z
    evidence:
    - reference: CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z
      reference_title: SAMD9L / SAMD9L-related spectrum and myeloid neoplasm risk (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SAMD9L | HGNC:1349 | SAMD9L-related spectrum and myeloid neoplasm risk | MONDO:1060111 | AD | Definitive"
      explanation: ClinGen Definitive autosomal dominant gene-disease validity for this MONDO term.
  evidence:
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results demonstrate that gain-of-function mutations in the tumor
      suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological
      presentation, and predisposition to MDS with -7/del(7q)
    explanation: Establishes germline gain-of-function SAMD9L variants as causal.
  - reference: PMID:39475954
    reference_title: "Genetic and clinical spectrum of SAMD9 and SAMD9L syndromes: from variant interpretation to patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients (>90%) carry germ line missense GoF variants. A subgroup of
      patients presenting with SAMD9L-associated inflammatory disease carry
      frameshift-truncating variants that are also GoF.
    explanation: >-
      Registry of 243 published SAMD9/SAMD9L patients; the missense fraction is
      pooled across both genes, the truncating-GoF statement is SAMD9L-specific.
  - reference: CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z
    reference_title: SAMD9L / SAMD9L-related spectrum and myeloid neoplasm risk (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of pathogenicity is reported to be gain of function for
      onset in childhood, loss of function for onset in adulthood (PMID:
      30322869).
    explanation: >-
      ClinGen's statement of the age-dependent mechanism split; the adult
      loss-of-function arm is discussed separately.
pathophysiology:
- name: SAMD9L Gain-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous germline missense variants, or C-terminal truncating
    frameshifts in SAAD, render SAMD9L constitutively more active as an
    antiproliferative factor. The germline variant is present in every cell,
    including non-hematopoietic tissue.
  genes:
  - preferred_term: SAMD9L
    term:
      id: hgnc:1349
      label: SAMD9L
  molecular_functions:
  - preferred_term: translation repressor activity
    term:
      id: GO:0030371
      label: translation repressor activity
    modifier: INCREASED
  evidence:
  - reference: PMID:34417303
    reference_title: SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Autoinflammatory disease associated with SAMD9L truncating mutations
      appears to result from an interferon-induced translational repressor
      whose activity goes unchecked by the loss of C-terminal domains that may
      normally sense virus infection.
    explanation: >-
      Describes SAMD9L as a translational repressor whose activity the
      truncating variants leave unchecked; grounds the molecular-function
      binding. Whether the repression is enzymatic is not stated in the cached
      sources.
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with a gain-of-function effect, ectopic expression of the 2
      identified SAMD9L mutants decreased cell proliferation relative to
      wild-type protein.
    explanation: Functional evidence that the patient alleles are gain-of-function.
  downstream:
  - target: Global Translational Repression
    causal_link_type: DIRECT
    description: >-
      Mutant SAMD9L, both truncating and ATXPC missense alleles, represses
      protein synthesis more strongly than wild type at the same expression
      level.
    evidence:
    - reference: PMID:34417303
      reference_title: SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The children's truncating mutations dramatically exaggerated
        translational repression even at low levels of GFP-SAMD9L per cell, as
        did a missense Arg986Cys mutation reported recurrently as causing ataxia
        pancytopenia syndrome.
      explanation: >-
        Shows the variant-to-translational-repression step for both SAAD and
        ATXPC alleles.
  - target: Cerebellar and Peripheral Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The neurologic disease follows from the constitutional variant in neural
      tissue rather than from the hematopoietic lesion: it persists when blood
      has been rescued and progresses after transplantation. The intermediate
      mechanism in neurons is unresolved.
    evidence:
    - reference: PMID:28202457
      reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinically, revertant mosaicism was associated with milder disease, yet
        neurological manifestations persisted in 3 individuals.
      explanation: >-
        Neurologic disease persists despite hematopoietic reversion, placing
        its origin in the constitutional variant outside blood.
    - reference: PMID:28570036
      reference_title: SAMD9L-Related Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        HSCT does not appear to halt the progression of non-hematologic
        manifestations.
      explanation: >-
        Transplantation corrects blood but not neurologic progression, again
        separating the two arms.
- name: Interferon-Driven SAMD9L Induction
  biological_scale: CELLULAR
  description: >-
    SAMD9L is an interferon-stimulated gene. Interferon signalling during
    infection raises expression of the mutant protein in hematopoietic
    progenitors and lymphocytes, which is proposed to explain why cytopenic and
    myelodysplastic episodes follow infections.
  biological_processes:
  - preferred_term: response to type I interferon
    term:
      id: GO:0034340
      label: response to type I interferon
  - preferred_term: cellular response to type II interferon
    term:
      id: GO:0071346
      label: cellular response to type II interferon
  evidence:
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced
      SAMD9L expression.
    explanation: Interferon-alpha and -gamma induce SAMD9L in B and NK cells.
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 developed MDS upon loss of the mutated SAMD9L allele following
      intracellular infections associated with myeloid, B-, and natural killer
      (NK)-cell deficiency.
    explanation: Clinical observation that MDS followed infections in carriers.
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings suggest a role for SAMD9L in regulating IFN-driven,
      demand-adapted hematopoiesis.
    explanation: >-
      The authors' interpretation; supports interferon-driven SAMD9L activity as
      a modifier of hematopoiesis, stated as a suggestion.
  downstream:
  - target: Global Translational Repression
    causal_link_type: DIRECT
    description: >-
      Interferon raises expression of the truncated SAAD protein, which then
      suppresses global protein synthesis.
    evidence:
    - reference: PMID:33724365
      reference_title: Germline SAMD9L truncation variants trigger global translational repression.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Taken together, our findings indicate that interferon-triggered SAMD9L
        gain-of-function variants globally suppress translation.
      explanation: Links interferon induction to the translational-repression step.
- name: Global Translational Repression
  biological_scale: CELLULAR
  description: >-
    Hyperactive SAMD9L inhibits translational elongation and globally
    suppresses protein synthesis cell autonomously, in proportion to its
    expression level.
  biological_processes:
  - preferred_term: negative regulation of translation
    term:
      id: GO:0017148
      label: negative regulation of translation
    modifier: INCREASED
  evidence:
  - reference: PMID:33724365
    reference_title: Germline SAMD9L truncation variants trigger global translational repression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This protein exhibited a gain-of-function phenotype, resulting in
      interference in global protein synthesis via inhibition of translational
      elongation.
    explanation: Mechanism of the translational block for a truncating SAMD9L allele.
  downstream:
  - target: Hematopoietic Progenitor Growth Restriction and Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The translation block is proposed to account for the lineage-dominant
      failure of hematopoietic progenitors and lymphocytes; the authors frame
      the lineage specificity as a sensitivity difference.
    evidence:
    - reference: PMID:33724365
      reference_title: Germline SAMD9L truncation variants trigger global translational repression.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The complex-reported phenotype likely reflects lineage-dominant
        sensitivities to this translation block.
      explanation: >-
        The authors' interpretation linking the translation block to the
        lineage-restricted phenotype; stated as likely, not shown.
  - target: Autoinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In SAAD, the unchecked translational repressor is proposed to underlie the
      autoinflammatory disease; how translation arrest produces inflammation is
      not established.
    evidence:
    - reference: PMID:34417303
      reference_title: SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Autoinflammatory disease associated with SAMD9L truncating mutations
        appears to result from an interferon-induced translational repressor
        whose activity goes unchecked by the loss of C-terminal domains that may
        normally sense virus infection.
      explanation: Authors' proposed link between translational repression and SAAD.
- name: Hematopoietic Progenitor Growth Restriction and Death
  biological_scale: CELLULAR
  description: >-
    Mutant SAMD9L suppresses proliferation of hematopoietic stem and progenitor
    cells and induces death of CD34+ cells, producing a hypocellular marrow
    with multilineage cytopenia. This growth block is also the selective
    pressure that favours any clone which loses or silences the mutant allele.
  cell_types:
  - preferred_term: CD34+ hematopoietic stem and progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: negative regulation of cell population proliferation
    term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:34621053
    reference_title: "Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed
      HEK293 cell growth, and mutations expressed in CD34+ cells induced overt
      cell death.
    explanation: >-
      Functional testing of patient alleles (pooled SAMD9 and SAMD9L) in a cell
      line and in CD34+ progenitors.
  - reference: PMID:33731850
    reference_title: Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      expression of these genes and their mutations leads to a cellular
      environment that promotes DNA damage repair defects and ultimately
      apoptosis in hematopoietic cells.
    explanation: >-
      Lentiviral expression of wild-type and mutant SAMD9/SAMD9L in primary
      mouse and human HSPCs; results are reported jointly for the two genes.
  downstream:
  - target: Pancytopenia
    causal_link_type: DIRECT
  - target: Thrombocytopenia
    causal_link_type: DIRECT
  - target: Neutropenia
    causal_link_type: DIRECT
  - target: Bone Marrow Hypocellularity
    causal_link_type: DIRECT
  - target: Maladaptive Somatic Rescue by Monosomy 7
    causal_link_type: DIRECT
    description: >-
      Cells that lose the chromosome 7 carrying the mutant allele escape the
      growth block and are positively selected.
    evidence:
    - reference: PMID:30046003
      reference_title: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces
        cell cycle progression, and deep sequencing demonstrated selective
        pressure favoring the outgrowth of clones that have either lost the
        mutant allele or acquired revertant mutations.
      explanation: >-
        Links the antiproliferative effect to selection of clones that lose the
        mutant allele.
  - target: Adaptive Somatic Rescue by UPD7q or In-cis SAMD9L Inactivation
    causal_link_type: DIRECT
    description: >-
      The same selective pressure favours clones that remove the mutant allele
      without losing the rest of chromosome 7.
    evidence:
    - reference: PMID:27259050
      reference_title: Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The hematopoietic cytopenias that characterize AP syndrome and the
        selective advantage for clones that have lost the mutant allele support
        the postulated role of SAMD9L in the regulation of cell proliferation.
      explanation: Selective advantage for clones that lose the mutant allele.
- name: Maladaptive Somatic Rescue by Monosomy 7
  biological_scale: CELLULAR
  description: >-
    Loss of chromosome 7 or 7q removes the mutant SAMD9L allele and relieves the
    growth block, but leaves the clone haploinsufficient for chromosome 7 genes
    including wild-type SAMD9L, SAMD9 and other 7q myeloid tumor suppressors.
    In young children the monosomy 7 clone can regress spontaneously
    (transient monosomy 7). Monosomy 7 has no HPO term, so it is modelled as
    this node rather than as a phenotype.
  evidence:
  - reference: PMID:39475954
    reference_title: "Genetic and clinical spectrum of SAMD9 and SAMD9L syndromes: from variant interpretation to patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic genetic rescue occurs in two-third of patients or more and
      involves monosomy 7, which may spontaneously disappear (transient
      monosomy 7) or progress to myelodysplastic syndrome (MDS)/leukemia
    explanation: >-
      Registry-level statement (pooled SAMD9/SAMD9L) of rescue frequency and the
      two fates of monosomy 7.
  - reference: PMID:34621053
    reference_title: "Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found that 61% of SAMD9/9Lmut patients underwent somatic genetic
      rescue (SGR) resulting in clonal hematopoiesis, of which 95% was
      maladaptive (monosomy 7 ± cancer mutations)
    explanation: >-
      Pediatric MDS cohort (n = 669) quantification of rescue; pooled SAMD9 and
      SAMD9L.
  - reference: PMID:29146883
    reference_title: A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SAMD9 and SAMD9L patients often experienced transient aplasia and
      monosomy 7
    explanation: >-
      Independent inherited marrow-failure cohort (germline DNA from skin
      fibroblasts); SAMD9 and SAMD9L reported together.
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within 14 months from diagnosis, three children experienced spontaneous
      hematological remission accompanied by a decrease in monosomy 7 clone
      size.
    explanation: Transient monosomy 7 in SAMD9L-specific infants (median age 0.6 years).
  downstream:
  - target: Myelodysplasia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28202457
      reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        3 developed MDS upon loss of the mutated SAMD9L allele following
        intracellular infections associated with myeloid, B-, and natural
        killer (NK)-cell deficiency.
      explanation: MDS arose with loss of the mutated allele.
  - target: Clonal Evolution with Cooperating Somatic Mutations
    causal_link_type: DIRECT
    description: >-
      Monosomy 7 clones can acquire cooperating driver mutations and progress.
    evidence:
    - reference: PMID:30046003
      reference_title: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The myeloid malignancies of affected siblings acquired cooperating
        mutations in genes that are also altered in sporadic cases of AML
        characterized by monosomy 7.
      explanation: Cooperating somatic mutations in monosomy 7 malignancies.
- name: Adaptive Somatic Rescue by UPD7q or In-cis SAMD9L Inactivation
  biological_scale: CELLULAR
  description: >-
    Copy-neutral loss of heterozygosity of 7q (uniparental disomy) that retains
    only the wild-type allele, or an acquired truncating SAMD9L variant in cis
    with the germline variant, restores hematopoiesis without loss of chromosome
    7. Revertant clones are associated with hematologic remission and milder
    disease, and can make a carrier appear unaffected. This is a protective
    terminal branch: it has no phenotype target because its consequence is the
    absence of cytopenia.
  evidence:
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five other individuals, 3 with spontaneously resolved cytopenic episodes
      in infancy, harbored hematopoietic revertant mosaicism by uniparental
      disomy of 7q, with loss of the mutated allele or additional in
      cisSAMD9L truncating mutations.
    explanation: >-
      Both adaptive mechanisms in SAMD9L carriers, with resolved infantile
      cytopenias. The missing space in "cisSAMD9L" is in the PubMed record.
  - reference: PMID:39475954
    reference_title: "Genetic and clinical spectrum of SAMD9 and SAMD9L syndromes: from variant interpretation to patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      adaptive clones with somatic SAMD9/9L compensatory mutations or
      uniparental disomy 7q (UPD7q), both associated with remission
    explanation: Registry-level statement that adaptive clones associate with remission.
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subclones with somatic SAMD9L mutations in cis were identified in five
      patients, three of whom attained hematological remission.
    explanation: >-
      In-cis somatic SAMD9L subclones in infants with monosomy 7; two of the
      five did not remit, so a rescue variant alone does not predict recovery.
      The image is the paper's longitudinal course for one patient (somatic
      in-cis variant fractions, monosomy 7 clone and neutrophil count).
    images:
    - SAMD9L-related_Spectrum_And_Myeloid_Neoplasm_Risk-deep-research-falcon_artifacts/image-1.png
- name: Clonal Evolution with Cooperating Somatic Mutations
  biological_scale: CELLULAR
  description: >-
    Monosomy 7 clones accumulate cooperating somatic driver mutations (RUNX1
    and EZH2 among those reported) and progress from refractory cytopenia to
    MDS with excess blasts or AML.
  evidence:
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients acquired RUNX1 and EZH2 mutations during the observation
      period, of whom one progressed to myelodysplastic syndrome with excess of
      blasts (MDS-EB).
    explanation: Acquisition of cooperating mutations and progression under surveillance.
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term observation revealed divergent outcomes with either progression
      to leukemia and/or accumulation of driver mutations (n=2), persistent
      monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous
      recovery with SAMD9L-wildtype UPD7q (n=2).
    explanation: Divergent clonal outcomes in familial SAMD9L MDS.
  downstream:
  - target: Myelodysplasia
    causal_link_type: DIRECT
  - target: Acute Myeloid Leukemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30046003
      reference_title: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected individuals had a highly variable clinical course that ranged
        from mild and transient dyspoietic changes in the bone marrow to a rapid
        progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia
        (AML) with monosomy 7.
      explanation: Progression to MDS or AML with monosomy 7.
- name: B and NK Lymphocyte Deficiency
  biological_scale: CELLULAR
  description: >-
    B and NK cells are disproportionately depleted, consistent with their high
    SAMD9L inducibility and with enrichment of revertant clones in these
    lineages. The resulting humoral and innate defect predisposes to
    infections. Whether those infections feed back on SAMD9L through interferon
    induction is plausible but not shown, so no edge is drawn for it.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Immunodeficiency most often consists of B and NK cell deficiencies.
    explanation: GeneReviews characterization of the immunodeficiency.
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic mutations were tracked to CD34+ hematopoietic progenitor cell
      populations, being further enriched in B and NK cells.
    explanation: >-
      Revertant somatic variants are enriched in B and NK cells, consistent with
      strong selection against the mutant allele in these lineages.
  downstream:
  - target: Decreased Total B Cell Count
    causal_link_type: DIRECT
  - target: Reduced Natural Killer Cell Count
    causal_link_type: DIRECT
  - target: Recurrent Infections
    causal_link_type: DIRECT
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
- name: Cerebellar and Peripheral Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Slowly progressive cerebellar degeneration with Purkinje-cell involvement,
    sensorimotor axonal neuropathy and cerebral white matter change. Neurologic
    onset is typically in adolescence or adulthood, later than the hematologic
    disease, and imaging changes can precede symptoms. In the SCA49 family
    SAMD9L localized to mitochondria and patient fibroblasts showed
    mitochondrial perturbation; in one SAAD infant autopsy showed selective
    Purkinje-cell loss. How SAMD9L variants damage neurons is unresolved.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The neurologic manifestations typically have later onset – during
      adolescence or less often adulthood – and include slowly progressive
      cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and
      paracentral retinal dysfunction.
    explanation: GeneReviews summary of the neurologic arm and its onset.
  - reference: PMID:33724365
    reference_title: Germline SAMD9L truncation variants trigger global translational repression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autopsy demonstrated absent bone marrow and peripheral B cells as well as
      selective loss of Langerhans and Purkinje cells.
    explanation: Neuropathologic Purkinje-cell loss in a SAAD infant (single case).
  - reference: PMID:35310830
    reference_title: New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate the mitochondrial location of human SAMD9L protein, and its
      decreased levels in patients' fibroblasts in addition to mitochondrial
      perturbations.
    explanation: Candidate mitochondrial mechanism, from the SCA49 family only.
  downstream:
  - target: Progressive Cerebellar Ataxia
    causal_link_type: DIRECT
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
  - target: Sensorimotor Neuropathy
    causal_link_type: DIRECT
  - target: Cerebral White Matter Abnormalities
    causal_link_type: DIRECT
  - target: Gaze-Evoked Nystagmus
    causal_link_type: DIRECT
  - target: Dysautonomia
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
- name: Autoinflammation
  biological_scale: ORGANISM
  description: >-
    In the SAAD subtype, neonatal- or infantile-onset systemic inflammation with
    an interferon-response gene signature that differs from the canonical
    interferonopathies, presenting as panniculitis, lipoatrophy, interstitial
    lung disease and basal ganglia calcification.
  subtypes:
  - SAAD
  evidence:
  - reference: PMID:31874111
    reference_title: Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG
      elevation that suggests prominent NF-κB activation different from the
      canonical interferonopathies CANDLE, SAVI, and AGS.
    explanation: Characterizes the inflammatory signature of SAAD.
  downstream:
  - target: Panniculitis
    causal_link_type: DIRECT
  - target: Lipoatrophy
    causal_link_type: DIRECT
  - target: Interstitial Lung Disease
    causal_link_type: DIRECT
  - target: Basal Ganglia Calcification
    causal_link_type: DIRECT
phenotypes:
- category: Hematologic
  name: Pancytopenia
  description: >-
    Cytopenias of all lineages in a hypocellular marrow, ranging from mild to
    severe and frequently fluctuating, usually first presenting in infancy or
    early childhood.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cytopenias affecting all hematopoietic lineages arise in a typically
      hypocellular marrow, range from mild to severe, and most often present in
      infancy or early childhood.
    explanation: GeneReviews description of the cytopenias and their onset.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Thrombocytopenia was the presenting finding in every patient of the
    familial MDS series, with or without other cytopenias.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with thrombocytopenia with or without additional
      cytopenias and a hypocellular marrow without an increase of blasts.
    explanation: Thrombocytopenia as the universal presenting cytopenia (n = 7).
- category: Hematologic
  name: Neutropenia
  description: >-
    Moderate to severe neutropenia. Reported in all seven children of a
    selected cohort (germline SAMD9L, monosomy 7, age under 5 years), so the
    proportion is not a population frequency.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At diagnosis, all patients had moderate to severe neutropenia and three
      children (P1, P2, P3) required platelet transfusions.
    explanation: Neutropenia at diagnosis in a selected cohort of seven children.
- category: Hematologic
  name: Bone Marrow Hypocellularity
  description: Typically hypocellular marrow without increased blasts at presentation.
  phenotype_term:
    preferred_term: Bone marrow hypocellularity
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with thrombocytopenia with or without additional
      cytopenias and a hypocellular marrow without an increase of blasts.
    explanation: Hypocellular marrow at presentation in the familial MDS series.
- category: Neoplasm
  name: Myelodysplasia
  description: >-
    Childhood MDS, most often refractory cytopenia of childhood, frequently
    with monosomy 7. In a consecutive pediatric MDS cohort germline
    SAMD9/SAMD9L variants (pooled) accounted for 8% of cases. Median age at
    diagnosis in the familial SAMD9L series was 2.1 years (range 1-42).
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:34621053
    reference_title: "Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS
      subtype (90%); acquired monosomy 7 was present in 38%
    explanation: MDS subtype and monosomy 7 frequency; pooled SAMD9 and SAMD9L.
  - reference: PMID:34621053
    reference_title: "Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8%
    explanation: Share of pediatric MDS explained by germline SAMD9/SAMD9L (pooled).
  - reference: PMID:29217778
    reference_title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Their median age at diagnosis was 2.1 years (range, 1-42).
    explanation: Onset age of MDS with chromosome 7 loss in SAMD9L families.
- category: Neoplasm
  name: Acute Myeloid Leukemia
  description: >-
    Progression to AML, usually with monosomy 7 and acquired cooperating
    mutations. This is the somatic neoplasm the germline syndrome predisposes
    to and is not itself curated as part of this entry.
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals have a predisposition to marrow failure, myelodysplasia, and
      myeloid leukemia, sometimes associated with monosomy 7.
    explanation: GeneReviews statement of myeloid leukemia predisposition.
- category: Immunologic
  name: Decreased Total B Cell Count
  phenotype_term:
    preferred_term: B-cell deficiency
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Immunodeficiency most often consists of B and NK cell deficiencies.
    explanation: GeneReviews.
- category: Immunologic
  name: Reduced Natural Killer Cell Count
  phenotype_term:
    preferred_term: NK-cell deficiency
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Immunodeficiency most often consists of B and NK cell deficiencies.
    explanation: GeneReviews.
- category: Immunologic
  name: Hypogammaglobulinemia
  description: >-
    Reported in five of seven children of a selected cohort (germline SAMD9L,
    monosomy 7, age under 5 years); not a population frequency.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most consistent findings of immunological impairment were
      hypogammaglobulinemia found in five patients (P1, P2, P5, P6, P7) and B-
      and natural killer (NK)-cell deficiency present in four (P2, P5, P6, P7).
    explanation: Hypogammaglobulinemia in a selected cohort of seven children.
- category: Immunologic
  name: Recurrent Infections
  description: >-
    Intracellular and other infections accompany the myeloid, B- and NK-cell
    deficiency and have preceded MDS in reported carriers.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:28202457
    reference_title: "Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 developed MDS upon loss of the mutated SAMD9L allele following
      intracellular infections associated with myeloid, B-, and natural killer
      (NK)-cell deficiency.
    explanation: Infections associated with the immune deficiency in carriers.
- category: Neurologic
  name: Progressive Cerebellar Ataxia
  description: >-
    Slowly progressive cerebellar ataxia, typically beginning in adolescence
    and less often in adulthood; absent in some carriers.
  phenotype_term:
    preferred_term: Slowly progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    onset:
      onset_category: JUVENILE
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The neurologic manifestations typically have later onset – during
      adolescence or less often adulthood – and include slowly progressive
      cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and
      paracentral retinal dysfunction.
    explanation: GeneReviews description and onset of the ataxia.
- category: Neurologic
  name: Cerebellar Atrophy
  description: Cerebellar atrophy on MRI, which may precede clinical ataxia.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Even before these manifestations are apparent, brain imaging may show
      cerebellar atrophy and periventricular and deep white matter
      abnormalities and/or cysts.
    explanation: GeneReviews imaging findings, preceding symptoms.
- category: Neurologic
  name: Cerebral White Matter Abnormalities
  description: >-
    Periventricular and deep white matter abnormalities and/or cysts on brain
    MRI, which may precede symptoms.
  phenotype_term:
    preferred_term: Periventricular and deep white matter abnormalities
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Even before these manifestations are apparent, brain imaging may show
      cerebellar atrophy and periventricular and deep white matter
      abnormalities and/or cysts.
    explanation: >-
      GeneReviews does not specify signal characteristics, so the general white
      matter morphology term is bound rather than a hyperintensity term.
- category: Neurologic
  name: Sensorimotor Neuropathy
  description: Sensorimotor axonal polyneuropathy.
  phenotype_term:
    preferred_term: Sensorimotor axonal polyneuropathy
    term:
      id: HP:0007141
      label: Sensorimotor neuropathy
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The neurologic manifestations typically have later onset – during
      adolescence or less often adulthood – and include slowly progressive
      cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and
      paracentral retinal dysfunction.
    explanation: GeneReviews.
- category: Neurologic
  name: Dysautonomia
  phenotype_term:
    preferred_term: Dysautonomia
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The neurologic manifestations typically have later onset – during
      adolescence or less often adulthood – and include slowly progressive
      cerebellar ataxia, sensorimotor axonal polyneuropathy, dysautonomia, and
      paracentral retinal dysfunction.
    explanation: GeneReviews.
- category: Neurologic
  name: Dysarthria
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:35310830
    reference_title: New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      affected individuals variably presenting with ataxia, nystagmus,
      dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and
      distinctive cerebral demyelination
    explanation: Dysarthria in the SCA49 family.
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      referral for speech and language therapy, including evaluation for
      alternative communication methods, as clinically indicated for dysarthria
    explanation: >-
      GeneReviews management of dysarthria across the syndrome; a management
      statement, not a frequency.
- category: Neurologic
  name: Gaze-Evoked Nystagmus
  description: >-
    Horizontal and vertical gaze-evoked nystagmus, an initial sign in the SCA49
    family.
  subtype: SCA49
  phenotype_term:
    preferred_term: Gaze-evoked nystagmus
    term:
      id: HP:0000640
      label: Gaze-evoked nystagmus
  evidence:
  - reference: PMID:35310830
    reference_title: New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: Initial sign and onset range in SCA49.
- category: Dermatologic
  name: Panniculitis
  description: Neonatal or infantile nodular panniculitis in SAAD.
  subtype: SAAD
  phenotype_term:
    preferred_term: Panniculitis
    term:
      id: HP:0012490
      label: Panniculitis
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:34417303
    reference_title: SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-genome sequencing of two children with leukocytoclastic
      panniculitis, basal ganglia calcifications, raised blood inflammatory
      markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells
      revealed heterozygous de novo SAMD9L mutations
    explanation: Panniculitis in two SAAD children.
- category: Dermatologic
  name: Lipoatrophy
  subtype: SAAD
  phenotype_term:
    preferred_term: Lipoatrophy
    term:
      id: HP:0100578
      label: Lipoatrophy
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This phenotype may include cytopenias, skin inflammation, lipoatrophy,
      early-onset interstitial lung disease, and basal ganglia calcifications.
    explanation: GeneReviews SAAD feature list.
- category: Respiratory
  name: Interstitial Lung Disease
  description: Early-onset interstitial lung disease in SAAD.
  subtype: SAAD
  phenotype_term:
    preferred_term: Interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This phenotype may include cytopenias, skin inflammation, lipoatrophy,
      early-onset interstitial lung disease, and basal ganglia calcifications.
    explanation: GeneReviews SAAD feature list.
- category: Neurologic
  name: Basal Ganglia Calcification
  subtype: SAAD
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:34417303
    reference_title: SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-genome sequencing of two children with leukocytoclastic
      panniculitis, basal ganglia calcifications, raised blood inflammatory
      markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells
      revealed heterozygous de novo SAMD9L mutations
    explanation: Basal ganglia calcification in two SAAD children.
diagnosis:
- name: Germline SAMD9L testing on non-hematopoietic DNA
  description: >-
    Diagnosis rests on a heterozygous germline SAMD9L gain-of-function variant.
    Because monosomy 7 or UPD7q can lower or erase the variant allele fraction
    in blood, marrow, buccal or saliva DNA, a negative or apparently somatic
    result in those tissues does not exclude the disease, and testing of a
    non-hematopoietic tissue may be needed.
  diagnosis_term:
    preferred_term: Germline genetic testing of non-hematopoietic tissue
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acquired monosomy 7 or uniparental disomy of 7q can reduce the variant
      allele frequency of a germline SAMD9L pathogenic variant in blood-, bone
      marrow-, buccal mucosa-, or saliva-derived DNA, leading to failure to
      identify the pathogenic variant or misclassification as somatic.
    explanation: GeneReviews diagnostic caveat specific to this disease.
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of SAMD9L-related syndrome is established in a proband with
      a heterozygous germline gain-of-function pathogenic variant in SAMD9L
      identified by molecular genetic testing.
    explanation: GeneReviews diagnostic criterion.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Considered for MDS, leukemia, severe immune deficiency or autoinflammatory
    manifestations. Timing is the central pediatric question, because monosomy
    7 can regress spontaneously in young children but delay carries risk of
    infection and progression. Transplantation does not halt the neurologic
    disease.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Hematopoietic Progenitor Growth Restriction and Death
    description: Replaces the SAMD9L-mutant hematopoietic compartment.
  - target: Clonal Evolution with Cooperating Somatic Mutations
    description: Eradicates monosomy 7 and malignant clones.
  - target: Autoinflammation
    description: >-
      Replaces the hematopoietic source of inflammation in SAAD; supported by a
      single case.
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      consider hematopoietic stem cell transplantation (HSCT) and/or
      chemotherapy for myelodysplasia, leukemia, severe immune deficiency, or
      autoinflammatory manifestations
    explanation: GeneReviews management recommendation.
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, they also indicate that delaying HSCT poses a substantial risk of
      severe infection and disease progression.
    explanation: Risk of deferring transplant in SAMD9L infants with monosomy 7.
  - reference: PMID:36969289
    reference_title: "Case report: De novo SAMD9L truncation causes neonatal-onset autoinflammatory syndrome which was successfully treated with hematopoietic stem cell transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient underwent a fully matched unrelated HSCT and has since been in
      inflammatory remission 5 years post-HSCT.
    explanation: >-
      Single SAAD case (p.F889Sfs*2) in sustained inflammatory remission after
      HSCT; a case report, not a response rate.
- name: Hematologic and Genetic Surveillance
  description: >-
    No established guideline exists. GeneReviews suggests hematology review and
    CBC every 6-12 months, baseline and annual marrow examination by shared
    decision, more frequent monitoring for new cytopenias or monosomy 7, and
    annual immunologic evaluation. In infants with monosomy 7, close genetic
    surveillance of clone size and acquired mutations is used to time HSCT.
  treatment_term:
    preferred_term: hematologic and cytogenetic surveillance
  notes: >-
    Left unbound: NCIT:C15719 Surveillance exists but is outside the
    TreatmentActionTerm dynamic enum.
  target_mechanisms:
  - target: Maladaptive Somatic Rescue by Monosomy 7
    description: Tracks monosomy 7 clone size and regression.
  - target: Clonal Evolution with Cooperating Somatic Mutations
    description: Detects acquisition of cooperating driver mutations.
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There are no established surveillance guidelines but suggested approaches
      include: clinical evaluation with a hematologist every six to 12 months
      depending on age and presence of cytopenias or monosomy 7; complete blood
      count with differential every six to 12 months; consider bone marrow
      evaluation at baseline and annually based on shared decision making with
      the individual and family
    explanation: GeneReviews suggested surveillance.
  - reference: PMID:37584291
    reference_title: "Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      surveillance of patients with SAMD9L syndrome and monosomy 7 is critical
      to define the evolving genetic landscape and to determine the appropriate
      timing of HSCT
    explanation: Surveillance-first approach in seven infants with monosomy 7.
- name: Transfusion Support
  description: Red cell and/or platelet transfusion for symptomatic cytopenias.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red cell and platelet transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide supportive care with red cell and/or platelet transfusions as
      needed
    explanation: GeneReviews supportive care.
- name: Corticosteroids or JAK Inhibitors for Autoinflammation
  description: >-
    Considered for autoinflammatory (SAAD) manifestations; supported by expert
    recommendation, not by trial data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: JAK inhibitor
      term:
        id: NCIT:C172200
        label: JAK Inhibitor
  target_mechanisms:
  - target: Autoinflammation
    description: Suppresses the inflammatory arm in SAAD.
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Consider corticosteroids or JAK inhibitors for autoinflammatory manifestations
    explanation: GeneReviews management recommendation.
- name: Immunoglobulin Replacement
  description: Considered to reduce infections that may exacerbate disease.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_mechanisms:
  - target: B and NK Lymphocyte Deficiency
    description: Replaces deficient humoral immunity.
  target_phenotypes:
  - preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      consider immunoglobulin replacement to reduce infections that may
      exacerbate disease
    explanation: GeneReviews management recommendation.
- name: Riluzole Trial for Ataxia
  description: >-
    A trial of riluzole may be considered for ataxia symptoms, alongside
    supportive rehabilitation; no SAMD9L-specific efficacy data are cited.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: riluzole
      term:
        id: CHEBI:8863
        label: Riluzole
  target_phenotypes:
  - preferred_term: Slowly progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: consider a trial of riluzole to improve ataxia symptoms
    explanation: GeneReviews management suggestion.
- name: Avoidance of Antiplatelet, Anticoagulant and Thrombolytic Agents in Severe Thrombocytopenia
  description: >-
    NSAIDs, anticoagulants and thrombolytics are contraindicated when
    thrombocytopenia is severe, and otherwise used with caution because the
    cytopenias fluctuate. An expert precaution, not a trial result.
  treatment_term:
    preferred_term: avoidance of NSAIDs, anticoagulants and thrombolytics
  notes: >-
    Left unbound. An OLS search of NCIT for "avoidance" returns NCIT:C54264
    Avoidance, which sits under Behavior/Activity rather than Clinical
    Intervention or Procedure, plus questionnaire items. NCIT:C15900 Lifestyle
    Therapy, used for avoidance rows elsewhere in the KB, names a lifestyle
    intervention rather than a drug contraindication.
  target_phenotypes:
  - preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic
      agents are contraindicated if severe thrombocytopenia is present and
      otherwise should be used with caution given the fluctuating nature of the
      cytopenias
    explanation: GeneReviews agents/circumstances to avoid.
- name: Avoidance of Alcohol and Sedating Medications
  description: >-
    Alcohol and centrally acting sedating medications can worsen gait and
    coordination in individuals with ataxia. An expert precaution.
  treatment_term:
    preferred_term: avoidance of alcohol and sedating medications
  notes: >-
    Left unbound for the same reason as the antithrombotic avoidance row.
  target_phenotypes:
  - preferred_term: Slowly progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      avoid alcohol and centrally acting medications that cause sedation, which
      can increase problems with gait and coordination
    explanation: GeneReviews agents/circumstances to avoid.
- name: Cascade Testing of At-Risk Relatives
  description: >-
    Testing for the familial variant identifies relatives who would benefit from
    hematologic surveillance. Because of somatic rescue, testing of relatives
    should use non-hematopoietic DNA when blood is negative.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling and cascade testing
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28570036
    reference_title: SAMD9L-Related Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Offer molecular genetic testing for the familial SAMD9L pathogenic variant
      to asymptomatic at-risk relatives to identify those who would benefit from
      hematologic surveillance and early treatment of severe cytopenias or
      myeloid malignancy.
    explanation: GeneReviews recommendation for relatives.
animal_models:
- name: Samd9l-deficient mouse
  species: Mouse
  genotype: Samd9l+/- and Samd9l-/-
  publication: PMID:24029230
  description: >-
    Heterozygous and homozygous Samd9l knockout mice develop myeloid disease
    resembling human -7/7q- disease. This is a loss-of-function model: it does
    not model the germline gain-of-function lesion, but models the consequence
    of losing one SAMD9L copy, which is part of what a monosomy 7 rescue clone
    carries.
  modeled_mechanisms:
  - target: Maladaptive Somatic Rescue by Monosomy 7
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces the myeloid consequence of SAMD9L haploinsufficiency that a
      monosomy 7 clone carries.
    limitations: >-
      Models loss of function, the opposite of the germline lesion; no
      gain-of-function background and no loss of the other chromosome 7 genes.
    evidence:
    - reference: PMID:24029230
      reference_title: "Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We established SAMD9L-deficient mice and found that SAMD9L(+/-) mice as
        well as SAMD9L(-/-) mice develop myeloid diseases resembling human
        diseases associated with -7/7q-.
      explanation: Samd9l loss in mice produces -7/7q-like myeloid disease.
discussions:
- discussion_id: adult_loss_of_function_arm
  kind: CONTROVERSY
  prompt: >-
    Do germline loss-of-function SAMD9L alleles in adult-onset myeloid
    neoplasms belong to this disease?
  attaches_to:
  - genetic#SAMD9L
  rationale: >-
    ClinGen's curation of MONDO:1060111 states that mechanism is gain of
    function for childhood onset and loss of function for adult onset, citing
    Nagata et al. 2018 (PMID:30322869). The pathograph here models only the
    gain-of-function chain. A loss-of-function allele would predispose by a
    different route (reduced tumor suppressor dosage, as in the Samd9l knockout
    mouse), with no growth restriction and no selection for rescue, and may be
    better modelled separately. The Nagata abstract is not available in the
    reference cache, so the adult arm is not curated as a claim.
  evidence:
  - reference: CGGV:assertion_1b553726-ca22-4116-bb50-373089ac4cb6-2025-01-14T170000.000Z
    reference_title: SAMD9L / SAMD9L-related spectrum and myeloid neoplasm risk (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of pathogenicity is reported to be gain of function for
      onset in childhood, loss of function for onset in adulthood (PMID:
      30322869).
    explanation: ClinGen statement of the two mechanisms.
- discussion_id: neurodegeneration_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How do germline SAMD9L variants cause cerebellar and peripheral
    neurodegeneration, and does the SCA49 allele act by gain or loss of
    function?
  attaches_to:
  - pathophysiology#Cerebellar and Peripheral Neurodegeneration
  rationale: >-
    The hematologic mechanism (translational repression and growth restriction
    relieved by somatic rescue) does not explain neurologic disease, which
    persists after hematopoietic rescue and transplantation. The SCA49 study
    reports decreased SAMD9L protein and mitochondrial perturbation in
    fibroblasts, which is not obviously a gain-of-function signature, while the
    ATXPC missense Arg986Cys is gain-of-function in translation assays. Whether
    one mechanism covers both, and whether neurons are sensitive to the same
    translation block, is not established.
- discussion_id: monosomy7_transplant_timing
  kind: OPEN_QUESTION
  prompt: >-
    In infants with SAMD9L disease and monosomy 7, when should surveillance give
    way to HSCT?
  attaches_to:
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation
  rationale: >-
    Monosomy 7 regresses spontaneously in some young children, but delay risks
    severe infection and progression; the cited series is small and there are
    no evidence-based surveillance protocols.
  evidence:
  - reference: PMID:39475954
    reference_title: "Genetic and clinical spectrum of SAMD9 and SAMD9L syndromes: from variant interpretation to patient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Future natural history studies, especially in patients with monosomy 7,
      will help formulate evidence-based surveillance protocols and optimize
      transplant timing and outcomes.
    explanation: Authors identify transplant timing as unresolved.
notes: >-
  GeneReviews (PMID:28570036, "SAMD9L-Related Syndrome") is the phenotype
  baseline. Its abstract also lists paracentral retinal dysfunction; that is
  not curated as a phenotype because the abstract does not name the test, and
  the matching HPO term (HP:0030489, abnormal paracentral response of
  multifocal electroretinogram) would assert a measurement the source does not
  report.
📚

References & Deep Research

References

1
PMID:28570036
SAMD9L-Related Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: SAMD9L-related_Spectrum_And_Myeloid_Neoplasm_Risk · 2026-10-13T19:28:24Z · View source

New entry for MONDO:1060111 (SAMD9L-related spectrum and myeloid neoplasm risk). Curated as one DISEASE entry with four has_subtypes rows: ATXPC (MONDO:0008038), M7MLS1 (MONDO:0009646) and SCA49 (MONDO:0030805), which ClinGen's CAYA Cancer Predisposition GCEP lumped into this MONDO term (cited from the cached CGGV record), plus SAAD (MONDO:0850066), included because the GeneReviews chapter (PMID:28570036) treats it as a subtype although the ClinGen lumping does not list it. SAMD9-related disease (MIRAGE and SAMD9-related myeloid predisposition) is excluded. HP:0001442 was not bound: the causal variant is germline, and the hematopoietic mosaicism is somatic genetic rescue, not a post-zygotic causal variant. The pathograph runs from the germline gain-of-function variant through translational repression and hematopoietic progenitor growth restriction to cytopenias, then branches into maladaptive rescue by monosomy 7 (leading to MDS and, with cooperating mutations, AML) and adaptive rescue by UPD7q or in-cis SAMD9L inactivation; separate branches cover B/NK deficiency, neurodegeneration (mechanism unknown, recorded as a knowledge gap) and SAAD autoinflammation. ClinGen Definitive AD tier copied from the cached CGGV record. GeneReviews abstract used as the phenotype baseline; paracentral retinal dysfunction is not curated as a phenotype (reason in entry notes). One falcon deep-research report was used as a lead only. A second falcon submission was started in error, after a log file shared with another session was misread as a failed first run; it was killed before it produced a report, and only the first run's report is committed. Its claim that MONDO:1060111 could not be confirmed was rejected (OLS and the ClinGen record confirm it). Its claims of neurologic onset from 10 to 62 years and Purkinje-cell loss in the original family were not used because they come from full-text pages not in the reference cache. Its 10/179 SAMD9L figure from the Bluteau cohort was not used because the abstract reports SAMD9 and SAMD9L pooled (16 of 86 diagnosed). Report validation: 8/8 references resolved, needs_review set only for a MONDO label mismatch caused by the template's '(if available)' text. preflight-dr exited 2 because the local mondo.db is absent; the report was checked by hand and is about SAMD9L throughout. Validation: just validate, validate-terms, count-verified-snippets (80/80), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-genereviews (TAGGED), list-gene-term-mismatches, check-block-scalar-comments, the whole-KB snippet/title/grading/retired-prose/environmental/coarse/reference-title gates, and validate-disorders all passed. Gaps: Nagata 2018 (PMID:30322869, adult germline loss-of-function) has no cached abstract, so the adult arm is recorded only as a discussion citing the ClinGen summary; several quantitative statements are pooled across SAMD9 and SAMD9L and are labelled as such; no population prevalence was found.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 34 citations 2026-10-13T19:17:29.688793

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: SAMD9L-Related Spectrum and Myeloid Neoplasm Risk
  • MONDO ID: MONDO:1060111 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on SAMD9L-Related Spectrum and Myeloid Neoplasm Risk covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
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For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

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  • Resources:
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Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

SAMD9L-related spectrum and myeloid-neoplasm risk

Scope and evidence standard. This is a disease-level synthesis of published families, selected clinical cohorts, cell experiments, model-organism findings, and trial registrations—not an analysis of an individual electronic health record. The most informative recent primary sources are a seven-child longitudinal cohort published online 17 August 2023 (print February 2024) and a neurological case series published 9 April 2024. Small, differently selected cohorts must not be pooled into a population penetrance or leukemia-risk estimate. (erlacher2023spontaneousremissionand pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)

1. Disease information and identifiers

SAMD9L-related disease is an autosomal-dominant, variably expressed spectrum encompassing ataxia–pancytopenia syndrome (ATXPC or AP syndrome), inherited marrow failure/cytopenias with immunodeficiency, predisposition to myelodysplastic neoplasms (MDS) and myeloid leukemia, and an uncommon severe neonatal autoinflammatory presentation. Neurological disease and cytopenias need not be equally severe in the same person. The founding study described AP syndrome as “characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia.” (chen2016ataxiapancytopeniasyndromeis pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 9-10, russell2021samd9lautoinflammatoryor pages 1-2)

Verified cross-references: OMIM phenotype MIM:159550 (ataxia–pancytopenia/myelocerebellar disorder); MONDO:0008038 (ataxia–pancytopenia syndrome); associated but not interchangeable entries MONDO:0009646 (monosomy-7 myelodysplasia and leukemia syndrome 1) and MONDO:0030805 (spinocerebellar ataxia 49). The user-supplied MONDO:1060111 could not be confirmed as the appropriate identifier and should not be entered as verified. An Orphanet identifier, syndrome-specific ICD-10/ICD-11 or MeSH identifier, and SAMD9L gene OMIM/HGNC accession were not confirmed from retrieved source material. The verified Ensembl gene identifier is ENSG00000177409. Synonyms include ataxia–pancytopenia syndrome, ATXPC, AP syndrome, myelocerebellar disorder, and, for particular presentations, SAMD9L-associated marrow-failure or autoinflammatory disease; these labels describe overlapping presentations, not necessarily identical diagnoses. (chen2016ataxiapancytopeniasyndromeis pages 1-2, OpenTargets Search: -SAMD9L)

2. Etiology, risk and protection

Primary cause. Heterozygous constitutional SAMD9L variants at 7q21.3 can increase the protein’s antiproliferative/translational-repression activity. Cases are familial or de novo. Established founding-family substitutions include c.2640C>A, p.His880Gln and c.3587G>C, p.Cys1196Ser; severe neonatal cases carry de novo frameshifts, including p.Asn885Thrfs*6, p.Lys878Serfs*13, and c.2666delT, p.Phe889Serfs*2. Variant-specific pathogenicity must be evaluated individually: a subsequently reported familial p.Gln1043Lys was explicitly classified as a variant of uncertain significance (VUS), not proven pathogenic. The original two substitutions were absent from the public population databases examined in 2016, but present-day gnomAD allele frequencies and ClinVar classifications for each variant were not verified here. (chen2016ataxiapancytopeniasyndromeis pages 1-2, russell2021samd9lautoinflammatoryor pages 1-2, caldirola2023casereportde pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)

Somatic modifiers are clinically decisive. A second-site inactivating SAMD9L variant in cis, or copy-neutral uniparental isodisomy of 7q replacing the mutant allele, can restore hematopoietic fitness without deleting the other chromosome-7 genes. By contrast, monosomy 7 or del(7q) may initially relieve mutant-allele growth inhibition but also removes other regulators/tumor suppressors, creating a dangerous route to MDS/AML. Acquired RUNX1 and EZH2 changes occurred during surveillance in the 2023–2024 cohort. Rescue mutations are potentially protective, not a guarantee of remission: they appeared in two children who did not recover. (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3, erlacher2023spontaneousremissionand pages 5-7, cobaleda2024insightsintothe pages 2-3)

Environment and gene–environment interaction. SAMD9L is interferon responsive, and interferon-β induces its RNA in experimental systems; infection-associated worsening of cytopenias was reported in one neonatal patient. Thus inflammation or infection is a biologically plausible amplifier of an inherited lesion, not a demonstrated necessary cause or quantified disease-specific leukemia risk factor. No SAMD9L-specific effect estimate establishes smoking, radiation, occupation, diet, alcohol or exercise as causal or protective. No dietary or pharmacological intervention is proven to prevent constitutional disease. (russell2021samd9lautoinflammatoryor pages 1-2, caldirola2023casereportde pages 1-2, cobaleda2024insightsintothe pages 2-3)

3. Phenotypes and quality of life

The following table describes children younger than five selected because they already had constitutional SAMD9L disease, monosomy 7 and initially normal marrow-blast percentages. Its fractions are not penetrance estimates or frequencies among all variant carriers. The paper’s Figure 1 illustrates how somatic-variant fractions, monosomy-7 clones and absolute neutrophil counts change over time in three remitting children; temporal association does not make a rescue variant a reliable individual prognostic test. (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3, erlacher2023spontaneousremissionand media d7f3e063, erlacher2023spontaneousremissionand pages 5-7)

Measure Fraction Interpretation
Moderate-to-severe neutropenia 7/7 (100%) Present in every child at diagnosis
Anemia 6/7 (86%) Five normocytic and one macrocytic case
Platelet-transfusion requirement 3/7 (43%) Indicates clinically significant thrombocytopenia
Any immunodeficiency 6/7 (86%) Variable clinical and laboratory immune impairment
Hypogammaglobulinemia 5/7 (71%) Most frequent specified immune abnormality
Combined B- and NK-cell deficiency 4/7 (57%) Reported jointly; not evidence that each deficiency independently occurred in 4/7
Spontaneous hematologic remission with monosomy-7 regression 3/7 (43%) Recovery occurred during close surveillance
Somatic SAMD9L subclones in cis 5/7 (71%) Putative genetic-rescue clones; presence did not reliably predict remission
Allogeneic HSCT 4/7 (57%) Performed for progression, persistent monosomy 7, severe neutropenia/infection, or a serious inflammatory complication
Progression to MDS with excess blasts 1/7 (14%) Occurred with acquired oncogenic evolution
Transplant-related death 1/7 (14%) Death followed HSCT rather than spontaneous disease progression
Interpretive limitation Selected cohort, n=7 Children aged <5 years were selected for germline SAMD9L disease, monosomy 7, and normal marrow blast percentage; fractions are not population prevalence or penetrance estimates (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3)

Table: Clinical findings and outcomes in the selected seven-child SAMD9L-plus-monosomy-7 cohort reported by Erlacher et al., DOI: https://doi.org/10.3324/haematol.2023.283591 (online August 17, 2023; print February 2024). These fractions characterize this narrowly selected cohort and are not population-level estimates.

Hematological signs/laboratory abnormalities: marrow hypocellularity, moderate-to-severe neutropenia, anemia (sometimes macrocytic), thrombocytopenia, pancytopenia and intermittent or progressive marrow failure can start in infancy; hemorrhage and serious infection are clinical consequences. Older families demonstrate that severe neurological involvement can accompany mild intermittent cytopenias and vice versa. Suggested HPO labels: bone marrow hypocellularity (verified HP:0005528), neutropenia, anemia, thrombocytopenia, pancytopenia, macrocytosis and myelodysplasia. Exact additional HP identifiers should be resolved against the current HPO release before database ingestion. (erlacher2023spontaneousremissionand pages 2-3, chen2016ataxiapancytopeniasyndromeis pages 9-10, chen2016ataxiapancytopeniasyndromeis pages 1-2, OpenTargets Search: -SAMD9L)

Immune and inflammatory signs: recurrent infection, hypogammaglobulinemia, B-/NK-cell deficiency, and—in the neonatal truncation phenotype—fever, panniculitis/neutrophilic skin inflammation, elevated inflammatory markers, hepatosplenomegaly, and sometimes basal-ganglia calcifications. Suggested HPO labels: recurrent infections, hypogammaglobulinemia, B-cell lymphopenia, fever, panniculitis and hepatosplenomegaly; do not generalize their neonatal severity to all carriers. (erlacher2023spontaneousremissionand pages 2-3, russell2021samd9lautoinflammatoryor pages 1-2, russell2021samd9lautoinflammatoryor pages 3-3, caldirola2023casereportde pages 1-2)

Neurological signs and functioning: progressive or initially subtle gait ataxia, nystagmus, dysmetria, brisk reflexes/clonus, cerebellar/brainstem atrophy and sometimes sensory axonal neuropathy. Onset ranges from childhood to adulthood: the original four-generation pedigree recorded neurological onset from 10 to 62 years; the 2024 six-person/two-family series found evolving balance and coordination deficits during serial observation. Walking, running and coordination may be affected; cytopenia/infection burdens can further disrupt ordinary activities. No syndrome-specific EQ-5D, SF-36 or robust quantified quality-of-life estimate was established. Suggested HPO labels: cerebellar ataxia, gait ataxia, nystagmus, dysmetria, hyperreflexia, cerebellar atrophy and peripheral neuropathy. (chen2016ataxiapancytopeniasyndromeis pages 3-4, zingariello2024assessinglong‐termneurologic pages 1-2)

4. Genetic and molecular information

The causal germline gene is SAMD9L, not its related paralog SAMD9: SAMD9 is important in the differential diagnosis and in overlapping combined-gene series, but MIRAGE syndrome due to SAMD9 should not be relabeled SAMD9L disease. Patient-associated SAMD9L classes include missense substitutions and unusually activating truncations. A truncating sequence consequence is not automatically functional loss of function: experimental tests found that the approximately residue-878–889 neonatal truncations produced stronger translational repression, plausibly through loss of C-terminal regulation. Allele-specific interpretation therefore requires segregation, germline confirmation, functional evidence and ACMG/AMP assessment. (chen2016ataxiapancytopeniasyndromeis pages 1-2, russell2021samd9lautoinflammatoryor pages 1-2, erlacher2023spontaneousremissionand pages 2-3)

Somatic versus inherited testing: somatic in-cis SAMD9L changes, mosaic -7/del(7q), and UPD7q can alter the variant-allele fraction in blood; a blood-only negative result may consequently be misleading. Confirm suspected germline findings in a suitable nonhematopoietic specimen and separate constitutional from acquired marrow variants. Additional chromosomal changes documented in an early family included monosomy 7 and trisomy 21 preceding AML. RUNX1/EZH2 are reported acquired cooperating lesions, not established inherited SAMD9L-specific modifier alleles. No reproducible syndrome-specific methylation, histone, proteomic, metabolomic or lipidomic signature was validated by the evidence examined. (chen2016ataxiapancytopeniasyndromeis pages 1-2, erlacher2023spontaneousremissionand pages 2-3, erlacher2023spontaneousremissionand pages 1-2)

5. Environmental information

The syndrome is genetic and not infectious or transmissible. Viral-defense/interferon biology supplies a plausible interaction with infection, while reported infections may also be a consequence of immune defects. Avoid assigning any particular bacterium, virus, toxin, radiation exposure, smoking habit or dietary pattern an established causal or protective role without new SAMD9L-specific data. (russell2021samd9lautoinflammatoryor pages 1-2, erlacher2023spontaneousremissionand pages 2-3)

6. Mechanism and pathophysiology: ordered causal chain

  1. Constitutional heterozygous activating SAMD9L variation leads to abnormally strong activity of an interferon-responsive antiviral protein; functional activation is shown for tested alleles, not assumed for every VUS. (russell2021samd9lautoinflammatoryor pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)
  2. Aberrant SAMD9L activity results in excessive cell-autonomous repression of protein translation; in hematopoietic stem/progenitor cells (HSPCs), this leads to reduced proliferation/colony output, cell-cycle disturbance and experimentally observed DNA-repair abnormalities and apoptosis. (russell2021samd9lautoinflammatoryor pages 1-2, thomas2021pediatricmdsand pages 1-2)
  3. Loss or poor function of progenitors results in hypocellular marrow, impaired blood-cell production, cytopenias and immune-cell deficits; immune impairment leads to increased infection burden. Attribution of every individual immune defect directly to translational repression is inferred, rather than demonstrated in each patient. (thomas2021pediatricmdsand pages 1-2, erlacher2023spontaneousremissionand pages 2-3)
  4. Growth disadvantage of mutant-bearing HSPCs leads to selection for clones that silence, lose or replace the constitutional allele: branch A: in-cis inactivating SAMD9L variants or copy-neutral UPD7q lead to potentially adaptive rescue and blood-count recovery. (erlacher2023spontaneousremissionand pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 1-2, cobaleda2024insightsintothe pages 2-3)
  5. Branch B: loss of mutant-bearing chromosome 7 or 7q leads to short-term clonal fitness, but results in coincident chromosome-7 gene loss; this increases susceptibility to dysplasia, additional acquired oncogenic lesions, MDS and occasionally AML. Individual progression is variable, not inevitable. (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3, cobaleda2024insightsintothe pages 2-3)
  6. Branch C: mutant effects on neural-cell biology are inferred to contribute to cerebellar/brainstem degeneration, neuropathy and ataxia; human pathology and imaging demonstrate injury, but a complete cell-type-specific molecular chain has not been established. In the severe truncation branch, amplified innate-immune dysfunction is inferred to contribute to neonatal systemic inflammation and tissue injury. (chen2016ataxiapancytopeniasyndromeis pages 9-10, zingariello2024assessinglong‐termneurologic pages 1-2, russell2021samd9lautoinflammatoryor pages 1-2)

Pathway and evidence detail. An interferon-induced antiviral response and translation control are more directly supported than assigning this syndrome to Wnt, PI3K–AKT or mTOR. The protein has predicted SAM, P-loop/NOD-like, tetratricopeptide-repeat and OB-fold regions; a proposed C-terminal sensing/regulatory function remains partly hypothetical. Human-cell single-cell expression assays documented dose-dependent translational inhibition; human/mouse primary-HSPC perturbation with protein-interaction and transcriptional analyses documented impaired proliferation, translation, DNA-damage response and survival. These are mechanistic experiments, not a validated diagnostic single-cell assay. Mouse deficiency studies implicate endosomal processing, but findings from loss-of-function mice must not be taken as direct proof of the mechanism of human gain-of-function ataxia. No established patient-specific enzyme deficiency, metabolic product, targeted proteomic signature, spatial-transcriptomic map or CRISPR-validated therapy emerged from the examined evidence. Suggested GO biological-process labels, identifier pending verification: response to type-I interferon, negative regulation of translation, regulation of cell proliferation, hematopoiesis, apoptotic process and endosomal transport. Suggested CL labels: hematopoietic stem cell, myeloid progenitor cell, neutrophil, B lymphocyte, natural-killer cell and cerebellar Purkinje cell; the last is supported by neuropathology rather than cell-specific mutant-function tests. (russell2021samd9lautoinflammatoryor pages 1-2, thomas2021pediatricmdsand pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 9-10)

7. Anatomical structures affected

Primary: bone-marrow hematopoietic tissue and, in neurological presentations, cerebellum/brainstem and peripheral nerves. Secondary: blood and immune system; severe neonatal presentations may involve skin/subcutis, liver/spleen, basal ganglia, respiratory tract and bowel. Cerebellar Purkinje-cell loss was documented in examined affected family members; B and NK cell reductions were measured in affected children. Relevant provisional UBERON labels are bone marrow, cerebellum, brainstem, peripheral nerve, skin and spleen; exact UBERON identifiers require ontology validation. Translation-associated cytoplasmic activity and endosomal biology are plausible GO cellular-component annotations, but no disease-specific organelle-localization map was verified. Disease is not defined by unilateral involvement; described neurological signs and imaging can be bilateral. (chen2016ataxiapancytopeniasyndromeis pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 9-10, erlacher2023spontaneousremissionand pages 2-3, russell2021samd9lautoinflammatoryor pages 3-3, thomas2021pediatricmdsand pages 1-2)

8. Temporal development

The course ranges from neonatal autoinflammation or infant cytopenias to insidious childhood/adult neurological disease. Marrow counts may fluctuate or improve spontaneously through somatic clonal selection, while ataxia can progress even if blood counts are comparatively mild. In the selected seven-child series, monosomy 7 disappeared by 6 and 16 months after diagnosis in two tracked children; three children achieved hematologic remission, but four ultimately needed transplantation. This creates an early-childhood observation opportunity only when rapid, specialist surveillance and a transplant contingency are available. There is no validated universal SAMD9L-specific early/intermediate/advanced staging scheme: describe marrow failure, lower- versus excess-blast MDS, and AML according to the applicable hematopathology classifications. (erlacher2023spontaneousremissionand pages 2-3, erlacher2023spontaneousremissionand pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)

9. Inheritance and population

Transmission is autosomal dominant, with familial and de novo presentations and substantial inter- and intrafamilial variable expressivity. Clinical penetrance, age-specific leukemia penetrance, carrier frequency, birth incidence and point prevalence cannot be reliably quantified from these ascertained series. Neither repeat-expansion anticipation nor a founder effect, consistent sex ratio, ethnic enrichment, consanguinity effect or natural germline mosaicism frequency was established. In one inherited-marrow-failure referral cohort, SAMD9L findings occurred in 10/179 (5.6%) patients and monosomy 7 in 5/10 affected patients: these are referral-cohort proportions, not population prevalence or universal lifetime risks. (chen2016ataxiapancytopeniasyndromeis pages 3-4, bluteau2018alandscapeof pages 9-13)

10. Diagnostics, differential diagnosis and screening

Clinical evaluation: serial complete blood count with differential, smear, reticulocyte and immunoglobulin assessment as indicated; B-/NK-cell immunophenotyping when immune disease is suspected; marrow aspirate/biopsy for cellularity, dysplasia and blast percentage; constitutional and marrow sequencing; karyotype and targeted chromosome-7 FISH, with SNP array when copy-neutral UPD7q is suspected. Track acquired myeloid variants and changing SAMD9L allele fractions. Brain MRI, formal neurological examination and serial motor testing assess ataxia; EMG/nerve studies assess suspected neuropathy. In the 2024 neurological series, a family’s p.Gln1043Lys remained a VUS, illustrating why phenotype alone must not upgrade a variant to pathogenic. (erlacher2023spontaneousremissionand pages 2-3, chen2016ataxiapancytopeniasyndromeis pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)

Genetic approach: include SAMD9L and SAMD9 on inherited marrow-failure/MDS-predisposition panels; WES/WGS are useful when panels are nondiagnostic or manifestations are broad. A single-gene test can address a known familial allele; test nonhematopoietic tissue when blood reversion or malignant contamination may obscure germline status. Conventional karyotyping detects -7, FISH tracks selected clones, and SNP-based methods resolve copy-neutral UPD. Mitochondrial sequencing and repeat-expansion tests are not routine confirmatory tests for this syndrome. RNA-seq, proteomics, metabolomics, epigenomics and liquid biopsy have no validated routine SAMD9L diagnostic role in the reviewed evidence. Differential diagnosis includes SAMD9-related MIRAGE, GATA2 deficiency and other inherited marrow-failure/MDS predispositions, and telomere disorders when cerebellar and marrow findings coexist; the original study distinguished AP syndrome from dyskeratosis congenita using additional clinical and cellular evidence. Cascade testing and donor evaluation require careful counseling because hematopoietic reversion can confound blood results. No population newborn-screening program was established. (erlacher2023spontaneousremissionand pages 2-3, chen2016ataxiapancytopeniasyndromeis pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2)

11. Outcome and prognosis

The principal hazards are severe infection or bleeding from cytopenias, progression to MDS/AML in vulnerable clones, and treatment-related complications. The small 2023–2024 series had six survivors among seven at last follow-up, including three untransplanted children with spontaneous hematologic recovery; one death was transplant-related. That fraction must not be expressed as a population survival rate. Persistent or enlarging -7 clones, increasing blasts and acquired oncogenic variants warrant concern; a second-site rescue variant alone does not establish a benign trajectory. Validated 5-/10-year SAMD9L-specific survival, lifetime cancer risk, life expectancy, disability and patient-reported quality-of-life estimates were not found. (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 5-7, erlacher2023spontaneousremissionand pages 2-3)

12. Treatment and real-world implementation

Strategy: use individualized pediatric hematology, genetics, immunology, neurology and transplant review. Support cytopenias and infections as clinically indicated, while repeatedly assessing marrow morphology, clone size and acquired variants. In selected very young children with normal blast counts, closely monitored observation can avoid immediate HSCT if -7 regresses; this is not reassurance that monosomy 7 is harmless. Erlacher and colleagues monitored marrow roughly every 3–4 months, and delayed transplantation carried risks of serious infection and progression. Allogeneic hematopoietic stem-cell transplantation (HSCT) may be necessary for progressive MDS/excess blasts, persistent high-risk disease or severe refractory cytopenia/infection; it can replace diseased hematopoiesis but entails graft, conditioning and transplant-mortality risks. Three of four transplanted children in the cohort were alive with stable engraftment at follow-up; one died from transplant complications. A separate de novo p.Phe889Serfs*2 neonatal autoinflammatory case remained in inflammatory remission five years after matched-unrelated HSCT—an individual case, not a response-rate estimate. (erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3, caldirola2023casereportde pages 1-2)

Supportive and investigational care: transfusion, infection treatment and immunological support should follow the measured defect; neurological rehabilitation, physical/occupational therapy and longitudinal balance testing can address functional limitations. A 12-day G-CSF course preceded rising blasts in one child who also acquired RUNX1 lesions: temporal association is not proof G-CSF caused progression, but this case requires cautious specialist interpretation. Neither a SAMD9L-specific small-molecule treatment, gene-editing intervention, RNA therapy, checkpoint inhibitor, nor variant-guided pharmacogenomic regimen has established clinical efficacy in the retrieved material. Suggested NCIT intervention labels, identifiers pending verification: hematopoietic stem cell transplantation, red blood cell transfusion, platelet transfusion, granulocyte colony-stimulating factor, and physical therapy; treosulfan, fludarabine, rabbit antithymocyte globulin, tacrolimus and methotrexate are regimen agents rather than syndrome-specific cures. (erlacher2023spontaneousremissionand pages 2-3, zingariello2024assessinglong‐termneurologic pages 1-2, NCT04965597 chunk 1)

Trials versus routine treatment: NCT00662090 is an observational childhood MDS/JMML registry, not an assigned SAMD9L treatment trial. NCT04965597 is a completed, phase-II, single-group, 40-participant transplant-conditioning study listing germline SAMD9L among eligible conditions and using treosulfan/fludarabine/rabbit antithymocyte globulin; the examined registry excerpt provided no SAMD9L-specific efficacy or safety results. (NCT00662090 chunk 1, NCT04965597 chunk 1)

13. Prevention and counseling

Primary prevention of a de novo or inherited allele by diet, vaccination or exposure modification is not established. Secondary prevention means recognizing inherited marrow failure, testing at-risk relatives, confirming constitutional status, and monitoring counts and chromosome-7/myeloid clones to identify treatable complications before advanced neoplasia. Tertiary prevention includes prompt infection/bleeding management and transplant when indicated. Genetic counseling should discuss autosomal-dominant transmission, variable manifestations and the possibility of blood-specific reversion; a related stem-cell donor must not be assumed unaffected without appropriate assessment. Prenatal/preimplantation testing can be discussed for a verified familial pathogenic variant, but a VUS must not be treated as a definitive diagnosis. Routine age-appropriate immunization is general supportive care, not a syndrome-specific preventive vaccine, with immune/transplant advice individualized. (chen2016ataxiapancytopeniasyndromeis pages 1-2, zingariello2024assessinglong‐termneurologic pages 1-2, erlacher2023spontaneousremissionand pages 1-2, erlacher2023spontaneousremissionand pages 2-3)

14. Other species and natural disease

The disease documented here occurs in humans (Homo sapiens; NCBI Taxon 9606); experimental research uses house mouse (Mus musculus; NCBI Taxon 10090). Ortholog nomenclature is human SAMD9L versus mouse Samd9l. Exact ortholog NCBI Gene accessions and VBO breed identifiers were not verified, and no convincing naturally occurring SAMD9L-defined veterinary disease, breed predisposition or zoonotic transmission was found. Mouse findings provide comparative biological insight, not evidence that this inherited disorder is contagious or present naturally in another species. (thomas2021pediatricmdsand pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 9-10, russell2021samd9lautoinflammatoryor pages 1-2)

15. Model organisms and experimental resources

Mouse genetic models: experimentally heterozygous/homozygous Samd9l deficiency has been reported to produce endosomal-processing defects and, in earlier work cited by the clinical investigators, myelodysplasia/myeloid malignancy at approximately 12 months. This models chromosome-7 gene loss and cancer predisposition, not faithfully the activating variant and progressive cerebellar disease of every human carrier; neurological deficits were not reported in the cited knockout comparison. A direct primary animal study should be consulted before depositing detailed model penetrance or strain-specific phenotype claims. Cellular models: human patient lymphoblastoid lines showed selection for cells retaining wild-type SAMD9L; transfected human cells allowed single-cell measurement of mutant-dependent translation suppression; lentivirally perturbed human/mouse HSPCs tested proliferation, translation, DNA-damage response and apoptosis. These systems are useful for variant-function assessment and the adaptive-versus-maladaptive clonal-rescue question, but do not establish a clinical gene-therapy protocol. Appropriate prospective resource labels are MGI/IMSR for verified mouse alleles, and Cellosaurus or laboratory repositories for verified cell-line accessions; specific accession numbers were not established. (chen2016ataxiapancytopeniasyndromeis pages 9-10, thomas2021pediatricmdsand pages 1-2, chen2016ataxiapancytopeniasyndromeis pages 1-2, russell2021samd9lautoinflammatoryor pages 1-2)

Selected source-linked abstract quotations and publication details

  • Chen et al., 2 June 2016, American Journal of Human Genetics, DOI 10.1016/j.ajhg.2016.04.009: “These observations indicate in vivo hematopoietic mosaicism.” Founding human-family evidence; OMIM phenotype 159550. PMID: not verified in retrieved text. (chen2016ataxiapancytopeniasyndromeis pages 1-2)
  • Russell et al., 20 August 2021, PNAS, DOI 10.1073/pnas.2110190118: “The children’s truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell.” Human cases plus in-vitro functional evidence. PMID: not verified. (russell2021samd9lautoinflammatoryor pages 1-2)
  • Thomas et al., 2021, Leukemia, DOI 10.1038/s41375-021-01212-6: “SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs.” Experimental human/mouse HSPC evidence. PMID: not verified. (thomas2021pediatricmdsand pages 1-2)
  • Erlacher et al., online 17 August 2023; print February 2024, Haematologica, DOI 10.3324/haematol.2023.283591: “Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size.” Longitudinal human clinical evidence, selected n=7. PMID: not verified. (erlacher2023spontaneousremissionand pages 1-2)
  • Zingariello et al., online 9 April 2024, Movement Disorders Clinical Practice, DOI 10.1002/mdc3.14038: “Patients with ATXPC should be followed to evaluate a wide range of neurologic manifestations.” Six-person human neurological case series, including a VUS-bearing family. PMID: not verified. (zingariello2024assessinglong‐termneurologic pages 1-2)
  • Caldirola et al., March 2023, Frontiers in Pediatrics, DOI 10.3389/fped.2023.1108207: “The patient underwent a fully matched unrelated HSCT and has since been in inflammatory remission 5 years post-HSCT.” Single human treatment case; PMID: not verified. (caldirola2023casereportde pages 1-2)

Knowledge-base qualification: The only HPO accession independently verified in the retrieved evidence was HP:0005528; only OMIM 159550, specified MONDO entries and ENSG00000177409 were verified for identifier mapping. Other requested HPO, GO, CL, UBERON, CHEBI and NCIT entries above are term-label suggestions rather than accession-validated annotations. CHEBI annotations for conditioning drugs should be resolved individually against chemical and drug registries. The accessible source excerpts did not reliably supply PMIDs; DOI-linked primary references are given instead of invented PMID numbers. Population incidence, age-specific penetrance, generalized leukemia risk and quantified treatment-response rates remain unresolved. (OpenTargets Search: -SAMD9L, chen2016ataxiapancytopeniasyndromeis pages 1-2, erlacher2023spontaneousremissionand pages 1-2, NCT04965597 chunk 1)

References

  1. (erlacher2023spontaneousremissionand pages 1-2): Miriam Erlacher, Felicia Andresen, Martina Sukova, Jan Stary, Barbara De Moerloose, Jutte van der Werff Ten Bosch, Michael Dworzak, Markus G. Seidel, Sophia Polychronopoulou, Rita Beier, Christian P. Kratz, Michaela Nathrath, Michael C. Frühwald, Gudrun Göhring, Anke K. Bergmann, Christina Mayerhofer, Dirk Lebrecht, Senthilkumar Ramamoorthy, Ayami Yoshimi, Brigitte Strahm, Marcin W. Wlodarski, and Charlotte M. Niemeyer. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with samd9l syndrome. Haematologica, 109:422-430, Aug 2023. URL: https://doi.org/10.3324/haematol.2023.283591, doi:10.3324/haematol.2023.283591. This article has 11 citations.

  2. (zingariello2024assessinglong‐termneurologic pages 1-2): Carla D. Zingariello, Dong‐Hui Chen, Wendy H. Raskind, William B. Slayton, Sub Subramony, Joyce Severance, Megan Feagle, and Sonja A. Rasmussen. Assessing long‐term neurologic outcomes in samd9l ‐related ataxia‐pancytopenia syndrome. Movement Disorders Clinical Practice, 11:728-733, Apr 2024. URL: https://doi.org/10.1002/mdc3.14038, doi:10.1002/mdc3.14038. This article has 1 citations and is from a peer-reviewed journal.

  3. (chen2016ataxiapancytopeniasyndromeis pages 1-2): Dong-Hui Chen, Jennifer E. Below, Akiko Shimamura, Sioban B. Keel, Mark Matsushita, John Wolff, Youngmee Sul, Emily Bonkowski, Maria Castella, Toshiyasu Taniguchi, Deborah Nickerson, Thalia Papayannopoulou, Thomas D. Bird, and Wendy H. Raskind. Ataxia-pancytopenia syndrome is caused by missense mutations in samd9l. American journal of human genetics, 98 6:1146-1158, Jun 2016. URL: https://doi.org/10.1016/j.ajhg.2016.04.009, doi:10.1016/j.ajhg.2016.04.009. This article has 236 citations and is from a highest quality peer-reviewed journal.

  4. (chen2016ataxiapancytopeniasyndromeis pages 9-10): Dong-Hui Chen, Jennifer E. Below, Akiko Shimamura, Sioban B. Keel, Mark Matsushita, John Wolff, Youngmee Sul, Emily Bonkowski, Maria Castella, Toshiyasu Taniguchi, Deborah Nickerson, Thalia Papayannopoulou, Thomas D. Bird, and Wendy H. Raskind. Ataxia-pancytopenia syndrome is caused by missense mutations in samd9l. American journal of human genetics, 98 6:1146-1158, Jun 2016. URL: https://doi.org/10.1016/j.ajhg.2016.04.009, doi:10.1016/j.ajhg.2016.04.009. This article has 236 citations and is from a highest quality peer-reviewed journal.

  5. (russell2021samd9lautoinflammatoryor pages 1-2): Amanda J. Russell, Paul E. Gray, John B. Ziegler, Yae Jean Kim, Sandy Smith, William A. Sewell, and Christopher C. Goodnow. Samd9l autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression. Proceedings of the National Academy of Sciences of the United States of America, Aug 2021. URL: https://doi.org/10.1073/pnas.2110190118, doi:10.1073/pnas.2110190118. This article has 45 citations and is from a highest quality peer-reviewed journal.

  6. (OpenTargets Search: -SAMD9L): Open Targets Query (-SAMD9L, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (caldirola2023casereportde pages 1-2): María Soledad Caldirola, Analía Gisela Seminario, Paula Carolina Luna, Renata Curciarello, Guillermo Horacio Docena, Nicolás Fernandez Escobar, Guillermo Drelichman, Marco Gattorno, Adriana A. de Jesus, Raphaela Goldbach-Mansky, María Isabel Gaillard, and Liliana Bezrodnik. Case report: de novo samd9l truncation causes neonatal-onset autoinflammatory syndrome which was successfully treated with hematopoietic stem cell transplantation. Frontiers in Pediatrics, Mar 2023. URL: https://doi.org/10.3389/fped.2023.1108207, doi:10.3389/fped.2023.1108207. This article has 3 citations.

  8. (erlacher2023spontaneousremissionand pages 2-3): Miriam Erlacher, Felicia Andresen, Martina Sukova, Jan Stary, Barbara De Moerloose, Jutte van der Werff Ten Bosch, Michael Dworzak, Markus G. Seidel, Sophia Polychronopoulou, Rita Beier, Christian P. Kratz, Michaela Nathrath, Michael C. Frühwald, Gudrun Göhring, Anke K. Bergmann, Christina Mayerhofer, Dirk Lebrecht, Senthilkumar Ramamoorthy, Ayami Yoshimi, Brigitte Strahm, Marcin W. Wlodarski, and Charlotte M. Niemeyer. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with samd9l syndrome. Haematologica, 109:422-430, Aug 2023. URL: https://doi.org/10.3324/haematol.2023.283591, doi:10.3324/haematol.2023.283591. This article has 11 citations.

  9. (erlacher2023spontaneousremissionand pages 5-7): Miriam Erlacher, Felicia Andresen, Martina Sukova, Jan Stary, Barbara De Moerloose, Jutte van der Werff Ten Bosch, Michael Dworzak, Markus G. Seidel, Sophia Polychronopoulou, Rita Beier, Christian P. Kratz, Michaela Nathrath, Michael C. Frühwald, Gudrun Göhring, Anke K. Bergmann, Christina Mayerhofer, Dirk Lebrecht, Senthilkumar Ramamoorthy, Ayami Yoshimi, Brigitte Strahm, Marcin W. Wlodarski, and Charlotte M. Niemeyer. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with samd9l syndrome. Haematologica, 109:422-430, Aug 2023. URL: https://doi.org/10.3324/haematol.2023.283591, doi:10.3324/haematol.2023.283591. This article has 11 citations.

  10. (cobaleda2024insightsintothe pages 2-3): Cesar Cobaleda, Lucy A. Godley, Kim E. Nichols, Marcin W. Wlodarski, and Isidro Sanchez-Garcia. Insights into the molecular mechanisms of genetic predisposition to hematopoietic malignancies: the importance of gene–environment interactions. Cancer Discovery, 14:396-405, Mar 2024. URL: https://doi.org/10.1158/2159-8290.cd-23-1091, doi:10.1158/2159-8290.cd-23-1091. This article has 30 citations and is from a highest quality peer-reviewed journal.

  11. (erlacher2023spontaneousremissionand media d7f3e063): Miriam Erlacher, Felicia Andresen, Martina Sukova, Jan Stary, Barbara De Moerloose, Jutte van der Werff Ten Bosch, Michael Dworzak, Markus G. Seidel, Sophia Polychronopoulou, Rita Beier, Christian P. Kratz, Michaela Nathrath, Michael C. Frühwald, Gudrun Göhring, Anke K. Bergmann, Christina Mayerhofer, Dirk Lebrecht, Senthilkumar Ramamoorthy, Ayami Yoshimi, Brigitte Strahm, Marcin W. Wlodarski, and Charlotte M. Niemeyer. Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with samd9l syndrome. Haematologica, 109:422-430, Aug 2023. URL: https://doi.org/10.3324/haematol.2023.283591, doi:10.3324/haematol.2023.283591. This article has 11 citations.

  12. (russell2021samd9lautoinflammatoryor pages 3-3): Amanda J. Russell, Paul E. Gray, John B. Ziegler, Yae Jean Kim, Sandy Smith, William A. Sewell, and Christopher C. Goodnow. Samd9l autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression. Proceedings of the National Academy of Sciences of the United States of America, Aug 2021. URL: https://doi.org/10.1073/pnas.2110190118, doi:10.1073/pnas.2110190118. This article has 45 citations and is from a highest quality peer-reviewed journal.

  13. (chen2016ataxiapancytopeniasyndromeis pages 3-4): Dong-Hui Chen, Jennifer E. Below, Akiko Shimamura, Sioban B. Keel, Mark Matsushita, John Wolff, Youngmee Sul, Emily Bonkowski, Maria Castella, Toshiyasu Taniguchi, Deborah Nickerson, Thalia Papayannopoulou, Thomas D. Bird, and Wendy H. Raskind. Ataxia-pancytopenia syndrome is caused by missense mutations in samd9l. American journal of human genetics, 98 6:1146-1158, Jun 2016. URL: https://doi.org/10.1016/j.ajhg.2016.04.009, doi:10.1016/j.ajhg.2016.04.009. This article has 236 citations and is from a highest quality peer-reviewed journal.

  14. (thomas2021pediatricmdsand pages 1-2): Melvin E. Thomas, Sherif Abdelhamed, Ryan Hiltenbrand, Jason R. Schwartz, Sadie Miki Sakurada, Michael Walsh, Guangchun Song, Jing Ma, Shondra M. Pruett-Miller, and Jeffery M. Klco. Pediatric mds and bone marrow failure-associated germline mutations in samd9 and samd9l impair multiple pathways in primary hematopoietic cells. Leukemia, 35:3232-3244, Mar 2021. URL: https://doi.org/10.1038/s41375-021-01212-6, doi:10.1038/s41375-021-01212-6. This article has 74 citations and is from a highest quality peer-reviewed journal.

  15. (bluteau2018alandscapeof pages 9-13): Olivier Bluteau, Marie Sebert, Thierry Leblanc, Régis Peffault de Latour, Samuel Quentin, Elodie Lainey, Lucie Hernandez, Jean-Hugues Dalle, Flore Sicre de Fontbrune, Etienne Lengline, Raphael Itzykson, Emmanuelle Clappier, Nicolas Boissel, Nadia Vasquez, Mélanie Da Costa, Julien Masliah-Planchon, Wendy Cuccuini, Anna Raimbault, Louis De Jaegere, Lionel Adès, Pierre Fenaux, Sébastien Maury, Claudine Schmitt, Marc Muller, Carine Domenech, Nicolas Blin, Bénédicte Bruno, Isabelle Pellier, Mathilde Hunault, Stéphane Blanche, Arnaud Petit, Guy Leverger, Gérard Michel, Yves Bertrand, André Baruchel, Gérard Socié, and Jean Soulier. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood, 131:717-732, Feb 2018. URL: https://doi.org/10.1182/blood-2017-09-806489, doi:10.1182/blood-2017-09-806489. This article has 322 citations and is from a highest quality peer-reviewed journal.

  16. (NCT04965597 chunk 1): Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904). Fred Hutchinson Cancer Center. 2022. ClinicalTrials.gov Identifier: NCT04965597

  17. (NCT00662090 chunk 1): Charlotte Niemeyer, MD. Study for Epidemiology and Characterization of Myelodysplastic Syndromes (MDS) and Juvenile Myelomonocytic Leucemia (JMML) in Childhood. University Hospital Freiburg. 2010. ClinicalTrials.gov Identifier: NCT00662090

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 6
Resolved 5
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:1060111 (2 mentions) - the report calls it "if available"; MONDO calls it SAMD9L-related spectrum and myeloid neoplasm risk

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MIM.