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SAMD9L-Related Ataxia-Pancytopenia Syndrome

, MD, , MD, PhD, , MD, PhD, and , MD.

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Estimated reading time: 16 minutes

Summary

Clinical characteristics.

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7. The onset of hematologic abnormalities has been reported as early as age three months. The cytopenias in all cell lineages ranged from mild to very severe. Onset of neurologic impairment is variable. Nystagmus, dysmetria, increased deep tendon reflexes, and clonus are common. Gait impairment and other neurologic abnormalities are slowly progressive.

Diagnosis/testing.

The diagnosis of SAMD9L-related ATXPC syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in SAMD9L on molecular genetic testing.

Management.

Treatment of manifestations: Red cell or platelet transfusions as needed for cytopenias; evaluation and treatment for additional unrelated causes of anemia; bone marrow transplantation and/or chemotherapy for myelodysplasia and leukemia; supportive management for ataxia to prevent falls and injury.

Surveillance: Annual complete blood count with more frequent monitoring for any identified cytopenia; prompt evaluation for clinical signs or symptoms of cytopenia; annual evaluation of gait, coordination, and speech.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias; avoid alcohol and medications that cause sedation, which can increase problems with gait and coordination.

Genetic Counseling.

SAMD9L-related ATXPC syndrome is inherited in an autosomal dominant manner. To date, no individuals diagnosed with SAMD9L-related ataxia-pancytopenia have the disorder as the result of a de novo SAMD9L pathogenic variant. Each child of an individual with SAMD9L-related ATXPC syndrome has a 50% chance of inheriting the SAMD9L pathogenic variant; intrafamilial clinical variability has been observed. Once the SAMD9L pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SAMD9L-related ATXPC syndrome and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome can be considered in an individual with any of the following clinical features, radiographic features, or family history, and suspected if more than one of these characteristics are present:

  • Cerebellar ataxia
  • Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
  • Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
  • Cerebellar atrophy and white matter changes on brain MRI examination
  • Family history of any of the above clinical or radiographic features

Establishing the Diagnosis

No formal clinical criteria for SAMD9L-related ATXPC syndrome have been established. The diagnosis of SAMD9L-related ATXPC syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in SAMD9L on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Perform sequence analysis of SAMD9L.
    Note: SAMD9L-related ATXPC syndrome is postulated to occur through a gain-of-function mechanism. Large intragenic deletion or duplication has not been reported; testing for intragenic deletion or duplication is not indicated.
  • A multigene panel that includes SAMD9L and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in SAMD9L-Related Ataxia-Pancytopenia Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
SAMD9LSequence analysis 34/4 families 4, 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome is a rare autosomal dominant condition characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7. Manifestations usually have onset in childhood and hematologic impairment can be severe, mimicking aplastic anemia or idiopathic thrombocytopenia purpura. There is marked inter- and intrafamilial variability in age of onset, severity of neurologic and hematologic abnormalities, and rate of progression. Only four families with molecularly confirmed SAMD9L-related ATXPC syndrome in a total of 25 individuals have been described [Li et al 1978, Li et al 1981, Chen et al 2016, Tesi et al 2017]; a fifth published family with a consistent phenotype is unavailable for molecular confirmation [Daghistani et al 1989].

Hematologic manifestations. Hematologic abnormalities are variable and can be intermittent. The onset of hematologic abnormalities has been reported as early as age three months.

The cytopenias in all cell lineages ranged from mild to very severe. Anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume [MCV]: 108 fl) were documented in many affected individuals. Immunodeficiency was documented in one family [Tesi et al 2017]. Non-leukemic marrows were hypoplastic in three individuals examined. Partial or complete monosomy 7 was found in marrow cells from four affected individuals, one of whom eventually developed leukemia [Li et al 1981]; two had myelodysplasia [Tesi et al 2017]. The effect of the disease on the hematopoietic system accounts for the increased mortality. In the four molecularly confirmed families, five affected individuals died in childhood from marrow failure and/or acute myeloid leukemia [Li et al 1981, Chen et al 2016]. Two children with myelodysplasia received matched unrelated marrow transplants and were alive 1.5 and seven years later [Tesi et al 2017].

In the family suspected to have ATXPC syndrome, one of three affected people had pancytopenia at age five years with mild macrocytosis (MCV 109 fl), decreased marrow cellularity, and monosomy 7 identified in marrow cells. This child died from acute myeloid leukemia that developed one year following diagnosis [Daghistani et al 1989].

Neurologic manifestations. Neurologic involvement was observed in all individuals with SAMD9L pathogenic variants who were carefully examined. Two individuals withSAMD9L pathogenic variants were not assessed neurologically [Tesi et al 2017] and one individual who was not noted to have neurologic problems during life had cerebellar atrophy detected on autopsy [Chen et al 2016]. Onset of neurologic impairment ranged from infancy to 62 years. Horizontal and vertical nystagmus and dysmetria were evident in most individuals. Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [Li et al 1978, Chen et al 2016, Tesi et al 2017]. Strength and sensation to touch and proprioception were preserved, but one individual had decreased vibration sense in the lower extremities [Li et al 1978]. Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually require a wheelchair [Chen et al 2016].

The severities of hematologic and neurologic abnormalities are not concordant. An individual who died at age 16 years from a retroperitoneal bleed secondary to thrombocytopenia had no clinically reported neurologic manifestations, despite the presence of cerebellar atrophy. Several individuals had moderate to severe neurologic involvement with only mild or undetected hematologic involvement [Li et al 1981, Chen et al 2016].

Neuroimaging and neuropathology. Eight individuals with a range of neurologic manifestations have been evaluated by brain imaging or autopsy. Marked cerebellar atrophy and loss of Purkinje cells were detected in four individuals, age seven to 16 years, in two families whose brains were examined postmortem. Moderate loss of neurons in the inferior olives and central nuclei was noted in two of these individuals [Li et al 1981, Chen et al 2016]. CT imaging of two of these children and their father revealed moderate to marked cerebellar atrophy at a time when their ataxia was described as mild to moderate [Li et al 1981]. At age 54 years, the surviving sib in this family had moderately severe ataxia and required a walker to ambulate. Brain MRI at age 52 years showed severe diffuse cerebellar atrophy as well as diffuse bilateral white matter signals throughout the cerebrum [Chen et al 2016].

In the second family reported by Chen et al [2016], brain MRIs revealed marked cerebellar degeneration, pronounced in the midline, in a man age 32 years with severe ataxia, and moderate midline cerebellar atrophy in his sister age 38 years, who had only mild clinical manifestations. Cerebellar atrophy and white matter abnormalities were also noted on MRI of two individuals reported by Tesi et al [2017].

Genotype-Phenotype Correlations

As only four families with identified pathogenic variants in SAMD9L have been reported, it is not possible to determine if there are genotype-phenotype correlations. Two of six affected individuals with pathogenic variant p.Cys1196Ser [Li et al 1978, Li et al 1981] and none of 17 with any of the other three known pathogenic variants [Chen et al 2016] have developed acute leukemia to date, but this tally does not include the two individuals who received marrow transplantation for myelodysplasia [Tesi et al 2017]. Somatic mosaicism for loss of the SAMD9L pathogenic variant has been documented in hematopoietic tissues of some individuals in three of the families [Chen et al 2016, Tesi et al 2017]. It is speculated that the presence of a clone that has uniparental disomy for the normal allele may ameliorate the severity of the hematologic manifestations [Tesi et al 2017].

Penetrance

To date, all 24 carefully assessed affected individuals in the four families with pathogenic variants in SAMD9L exhibited clinical manifestations. One individual without hematologic cytopenias was not neurologically examined. Expressivity of both hematologic and neurologic manifestations is extremely variable and shows no difference for males and females.

Nomenclature

The disorder was initially called myelocerebellar syndrome by Li et al [1978].

Prevalence

True prevalence is unknown, but the disorder is extremely rare. To the authors' knowledge, only four families with molecularly confirmed ataxia-pancytopenia syndrome have been described in the scientific literature [Li et al 1978, Chen et al 2016, Tesi et al 2017].

Differential Diagnosis

As with other ataxias, it is important to consider acquired causes, as they may be amenable to targeted treatment, and other inherited cerebellar ataxias, as there is considerable overlap in neurologic manifestations (see Ataxia Overview).

Because the prominent medical problem in many individuals with ATXPC syndrome is hematopoietic cytopenias, and neurologic impairment may be minimal, acquired bone marrow failure syndromes such as aplastic anemia or idiopathic thrombocytopenia purpura would also be included in the differential diagnosis.

Table 2.

Disorders to Consider in the Differential Diagnosis of SAMD9L-Related Ataxia-Pancytopenia Syndrome

DisorderGene(s)MOIHematologic ManifestationsNeurologic ManifestationsOther
X-linked sideroblastic anemia and ataxiaABCB7XL
  • Moderate hypochromic & microcytic anemia w/out progression to marrow failure
  • Not associated w/malignancy
Spinocerebellar syndrome in males 1
Ataxia-telangiectasiaATMAR
  • Bone marrow failure
  • Increased risk for malignancy, particularly lymphocytic leukemia & lymphoma
  • Progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis
  • Early-onset dystonia in non-classic form
  • Immunodeficiency
  • Sensitivityto ionizing radiation
  • Telangiectasias
Fanconi anemiaSee footnote 2AR
AD
XL
  • Progressive bone marrow failure
  • Myelodysplasia
  • Acute myeloid leukemia
  • Microcephaly
  • Ophthalmic abnormalities
  • Solid tumors
  • Congenital abnormalities 3
  • Chromosome breakage/radial forms on lymphocyte cytogenetic testing w/DEB & MMC
Dyskeratosis congenitaSee footnote 4XL
AD
AR
  • Progressive bone marrow failure
  • Myelodysplasia
  • Acute myeloid leukemia
Normal psychomotor development & neurologic function in most persons; see footnote 5 for exceptions
  • Dysplastic nails
  • Lacy reticular pigmentation
  • Oral leukoplakia
  • Squamous cell carcinomas
  • Other solid tumors
  • Pulmonary fibrosis
Familial monosomy 7 syndromen/aUnknown
  • Bone marrow insufficiency/failure
  • Acute myeloid leukemia
  • Myelodysplasia
None
MIRAGE syndrome (OMIM 617053)SAMD9AD
  • Myelodysplasia
  • Cytopenias
Cognitive impairment
  • Adrenal hypoplasia
  • Growth restriction
  • Enteropathy
  • Genital abnormalities

AR = autosomal recessive; AD = autosomal dominant; DEB = diepoxybutane; MMC = mitomycin C; MOI = mode of inheritance; XL = X-linked

1.

Spinocerebellar syndrome in males manifest primarily as delayed walking, ataxia evident in early childhood, dysmetria, and dysdiadochokinesis. When present the intention tremor is mild and the dysarthria is mild to moderately severe. The ataxia has been described as either non-progressive or slowly progressive.

2.

Genes known to be associated with Fanconi anemia include BRCA2, BRIP1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51C, SLX4, and UBE2T.

3.

The majority of individuals with FA have congenital abnormalities, most commonly short stature and skeletal, craniofacial, and genitourinary tract malformations. Abnormal skin pigmentation and microcephaly are also common. Other anomalies include developmental delay, hearing loss, congenital heart disease, and CNS anomalies.

4.

To date, ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53 are the genes in which pathogenic variants are known to cause dyskeratosis congenita.

5.

Significant developmental delay is present in the two clinical variants – Hoyeraal-Hreidarsson syndrome and Revesz syndrome – in which additional findings include, respectively: cerebellar hypoplasia and ataxia; and bilateral exudative retinopathy and intracranial calcifications.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome, the following evaluations are recommended if they have not already been completed:

  • Medical history and physical examination including neurologic examination
  • Brain MRI examination and referral to a neurologist
  • Complete blood count with differential
  • Referral to a hematologist/oncologist; bone marrow examination including chromosome 7-targeted FISH if hematologic abnormalities are more than minimal
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hematologic manifestations

  • Management of hematologic impairment is based on the severity of cytopenias and consists of red cell or platelet transfusions as needed.
  • Evaluate and treat for unrelated causes of anemia such as iron and vitamin deficiencies.
  • Marrow transplantation for myelodysplasia was successful in two individuals to date.

Note: There are no data to support use of erythropoietin or granulocyte-stimulating factor in SAMD9L-related ATXPC syndrome; these growth factors may increase the risk for myelodysplasia and myeloid leukemia.

Neurologic manifestations. Management of ataxia is supportive, as there is no known therapy to delay or halt the progression of the disease.

  • Individuals should continue to be active and use canes and walkers to prevent falls.
  • Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
  • Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

Surveillance

The following are appropriate:

  • Complete blood count annually. If cytopenias are identified, these should be monitored more frequently.
  • Patient/family education to seek prompt clinical evaluation if any signs or symptoms suggestive of hematopoietic cytopenia develop (e.g., fatigue, pallor, unexpected bleeding, recurrent infections).
  • Annual evaluation of gait, coordination, and speech.

Agents/Circumstances to Avoid

Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias.

Avoid consuming alcohol and medications that cause sedation, which can increase problems with gait and coordination.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the SAMD9L pathogenic variant in the family in order to identify as early as possible those who would benefit from hematologic surveillance and prompt initiation of treatment for severe cytopenias and myelodysplasia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no information of the effect of pregnancy on manifestations of SAMD9L-related ATXPC syndrome. Anemia, thrombocytopenia, or neutropenia may increase the risk of pregnancy complications.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • All affected individuals (for whom relevant parental information was available) in the four families with confirmed SAMD9L-related ATXPC syndrome have an affected parent. Marked intrafamilial variation in terms of age of onset, neurologic manifestations, and hematologic abnormalities is reported in all of these families.
  • To date, no individuals diagnosed with SAMD9L-related ATXPC syndrome have the disorder as the result of a de novo SAMD9L pathogenic variant.
  • Recommendations for the evaluation of apparently asymptomatic parents of a proband include SAMD9L molecular genetic testing.
  • Theoretically, the family history of an individual diagnosed with SAMD9L-related ATXPC syndrome may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Although not yet definitively observed, reduced penetrance is possible. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with SAMD9L-related ATXPC syndrome has a 50% chance of inheriting the SAMD9L pathogenic variant; intrafamilial clinical variability has been observed (see Clinical Description).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SAMD9L pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SAMD9L pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SAMD9L-related ATXPC syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Aplastic Anemia & MDS International Foundation, Inc.
    100 Park Avenue
    Suite 108
    Rockville MD 20850
    Phone: 800-747-2820; 301-279-7202
    Fax: 301-279-7205
    Email: help@aamds.org; info@aamds.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SAMD9L-Related Ataxia-Pancytopenia Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SAMD9L-Related Ataxia-Pancytopenia Syndrome (View All in OMIM)

159550ATAXIA-PANCYTOPENIA SYNDROME; ATXPC
611170STERILE ALPHA MOTIF DOMAIN-CONTAINING PROTEIN 9-LIKE; SAMD9L

Molecular Genetic Pathogenesis

The role of SAMD9L in human bone marrow failure and malignancies is not known with certainty. Many lines of evidence showed that SAMD9L has a role in cell proliferation, most likely as a tumor suppressor. The levels of expression of SAMD9L in breast cancer tissue and hepatocellular carcinomas are lower than in normal breast or liver tissue from the same individuals [Li et al 2007, Wang et al 2014]. Somatic pathogenic variants clustered in the coding region of SAMD9L have been identified in hepatitis-B-related hepatocellular carcinomas [Huang et al 2012, Wang et al 2014]. There is enhanced proliferation and colony formation of multiple hepatocellular carcinoma cell lines and increased tumorigenicity in nude mice after knockdown of Samd9l, the ortholog of SAMD9L, by siRNA or shRNA [Wang et al 2014]. Loss of one or both copies of Samd9l predisposed the mice to develop myelodysplasia [Nagamachi et al 2013]. Studies in EBV-transformed leukocyte cell lines [Chen et al 2016] and transiently transfected HEK293 cells [Tesi et al 2017] provided evidence that cells diploid for wild type SAMD9L have a selective culture advantage over those heterozygous for mutated SAMD9L. The detection in multiple affected individuals in three families of hematopoietic clones with copy-neutral loss of heterozygosity for the mutated allele supports a survival advantage in vivo as well [Chen et al 2016, Tesi et al 2017]. The fact that the four known pathogenic variants in SAMD9L are not in the sterile alpha motif domain suggests that the pathogenesis of SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome is not driven by the sterile alpha motif.

In individuals with SAMD9L-related ATXPC syndrome, marrow hypocellularity without dysplastic features reflects a toxic gain of function with suppression of precursor cell divisions. In contrast, consistent with what was observed in mice, haploinsufficiency for SAMD9L through monosomy of 7 or 7q predisposed to myelodysplasia [Li et al 2012, Tesi et al 2017]. Interestingly, loss of the mutated SAMD9 allele via monosomy 7 led to myelodysplasia in two individuals with MIRAGE syndrome [Narumi et al 2016]. It is speculated that transformation to acute myeloid leukemia requires additional mutations.

The neurologic component of SAMD9L-related ATXPC syndrome possibly results from a toxic gain of function, given that neurologic deficits were not described and presumably not present in Samd9l knockout mice [Li et al 2012, Chen et al 2016].

Gene structure. SAMD9L encompasses 18 kb of genomic DNA. The longest transcript variant NM_152703.3 has five exons, but exons 1-4 are noncoding.

Interestingly, SAMD9L is contiguous to paralogous gene SAMD9, in which defects cause the unrelated syndromes normophosphatemic familial tumoral calcinosis (OMIM 610455) [Topaz et al 2006] and the MIRAGE syndrome (OMIM 617053) [Narumi et al 2016].

Pathogenic variants. Four pathogenic variants, c.2640C>A, c.3587G>C, c.2672T>C, and c.2956C>T, have been identified to date, each in a single family [Chen et al 2016, Tesi et al 2017].

Table 3.

SAMD9L Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2640C>Ap.His880GlnNM_152703​.3
NP_689916​.2
c.2672T>Cp.Ile891Thr
c.2956C>Tp.Arg986Cys
c.3587G>Cp.Cys1196Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The 7.1 kb mRNA of transcript variant NM_152703.3 encodes 1,584 amino acids. Amino acids 14 to 79 comprise the sterile alpha motif domain.

Abnormal gene product. It is postulated that the four known pathogenic variants increase the function of SAMD9L protein to suppress normal hematopoiesis. The neurologic component of SAMD9L-related ATXPC syndrome possibly results from a toxic gain of function (see Molecular Genetic Pathogenesis).

References

Literature Cited

  • Chen DH, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, Sul Y, Bonkowski E, Castella M, Taniguchi T, Nickerson D, Papayannopoulou T, Bird TD, Raskind WH. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146–58. [PMC free article: PMC4908176] [PubMed: 27259050]
  • Daghistani D, Curless R, Toledano SR, Ayyar DR. Ataxia-pancytopenia and monosomy 7 syndrome. J Pediatr. 1989;115:108–10. [PubMed: 2738778]
  • Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, Zhu ZD, Zhou B, Liu XY, Liu RF, Fei QL, Chen H, Cai B, Zhou B, Xiao HS, Qin LX, Han ZG. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44:1117–21. [PubMed: 22922871]
  • Li CF, Macdonald JR, Wei RY, Ray J, Lau K, Kandel C, Koffman R, Bell S, Scherer SW, Alman BA. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics. 2007;8:92. [PMC free article: PMC1855325] [PubMed: 17407603]
  • Li FP, Hecht F, Kaiser-Mccaw B, Baranko PV, Potter NU. Ataxia-pancytopenia: syndrome of cerebellar ataxia, hypoplastic anemia, monosomy 7, and acute myelogenous leukemia. Cancer Genet Cytogenet. 1981;4:189–96. [PubMed: 6947857]
  • Li FP, Potter NU, Buchanan GR, Vawter G, Whang-Peng J, Rosen RB. A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy. Am J Med. 1978;65:933–40. [PubMed: 283689]
  • Li Q, Guo H, Matsui H, Honda H, Inaba T, Sundberg JP, Sprecher E, Uitto J. Mouse Samd9l is not a functional paralogue of the human SAMD9, the gene mutated in normophosphataemic familial tumoral calcinosis. Exp Dermatol. 2012;21:554–6. [PMC free article: PMC3381902] [PubMed: 22716256]
  • Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, Takubo K, Suda T, Nakamura T, Wolff L, Honda H, Inaba T. Haploinsufficiency of SAMD9L, an endosome fusion facilitator causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24:305–17. [PubMed: 24029230]
  • Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, Toyoshima K, Tanaka Y, Fukuzawa R, Miyako K, Kinjo S, Ohga S, Ihara K, Inoue H, Kinjo T, Hara T, Kohno M, Yamada S, Urano H, Kitagawa Y, Tsugawa K, Higa A, Miyawaki M, Okutani T, Kizaki Z, Hamada H, Kihara M, Shiga K, Yamaguchi T, Kenmochi M, Kitajima H, Fukami M, Shimizu A, Kudoh J, Shibata S, Okano H, Miyake N, Matsumoto N, Hasegawa T. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7. [PubMed: 27182967]
  • Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, Komulainen-Ebrahim J, Gorcenco S, Rundberg Nilsson A, Ripperger T, Kokkonen H, Bryder D, Fioretos T, Henter JI, Möttönen M, Niinimäki R, Nilsson L, Pronk CJ, Puschmann A, Qian H, Uusimaa J, Moilanen J, Tedgård U, Cammenga J, Bryceson YT. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129:2266–79. [PMC free article: PMC5399482] [PubMed: 28202457]
  • Topaz O, Indelman M, Chefetz I, Geiger D, Metzker A, Altschuler Y, Choder M, Bercovich D, Uitto J, Bergman R, Richard G, Sprecher E. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet. 2006;79:759–64. [PMC free article: PMC1592555] [PubMed: 16960814]
  • Wang Q, Zhai YY, Dai JH, Li KY, Deng Q, Han ZG. SAMD9L inactivation promotes cell proliferation via facilitating G1-S transition in hepatitis B virus-associated hepatocellular carcinoma. Int J Biol Sci. 2014;10:807–16. [PMC free article: PMC4115192] [PubMed: 25076857]

Author Notes

Website: www.gs.washington.edu/faculty/raskind.htm

The focus of research in the Raskind laboratory is to find and study genes responsible for inherited neurologic disorders. In a long-standing collaboration with Dr. Thomas Bird, we identified ABCB7 for X-linked sideroblastic anemia with ataxia, PRKCG for SCA14, ATP6AP2 for X-linked parkinsonism with spasticity, and ADCY5 for ADCY5-related dyskinesia, in addition to SAMD9L for ATXPC syndrome.

Revision History

  • 1 June 2017 (sw) Review posted live
  • 5 December 2016 (wr) Original submission
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