SAMD9L – Ataxia-Pancytopenia Syndrome

Ataxia-pancytopenia syndrome (MONDO_0008038) is an autosomal dominant disorder caused by heterozygous gain-of-function variants in the sterile alpha motif domain-containing 9-like gene, SAMD9L. It manifests with cerebellar ataxia, demyelinating peripheral neuropathy, conjunctival telangiectasia, and variable hematologic cytopenias progressing to bone marrow failure. Somatic compensatory events such as loss of heterozygosity on chromosome 7q modulate clinical severity.

Pathogenic missense variants clustering in the SAM domain have been identified in both familial and sporadic cases. In the four-generation UW-AP pedigree, two cosegregating changes—c.2640C>A (p.His880Gln) and c.3587G>C (p.Cys1196Ser)—fully segregated with disease across affected relatives (PMID:27259050). A de novo variant, c.2686C>G (p.Phe896Val), was reported in a patient with predominantly neurological features (PMID:31053103).

To date, at least 38 unrelated probands harboring SAMD9L gain-of-function mutations have been described (PMID:32808377). The recurrent hotspot variant c.2956C>T (p.Arg986Cys) appears in multiple families and demonstrates high penetrance of neurologic and hematologic phenotypes.

Functional studies reveal that SAMD9L gain-of-function mutants augment the protein’s antiproliferative activity by inhibiting translation elongation. Translational repression assays in cell models confirm a global block in protein synthesis (PMID:33724365, PMID:34417303). Mouse models of Samd9l alteration recapitulate human bone marrow hypocellularity and myeloid transformation, supporting a combined gain-of-function and haploinsufficiency mechanism (PMID:24029230).

Diagnostic pitfalls include clonal elimination of the pathogenic allele in peripheral blood, leading to false-negative results unless allele-specific or non-hematopoietic tissue testing is performed (PMID:36553623).

No studies have definitively refuted the SAMD9L–ataxia-pancytopenia association. The reproducibility of genetic segregation, de novo occurrences, and concordant functional data across independent cohorts solidifies a strong clinical validity.

Key Take-home: Heterozygous gain-of-function SAMD9L variants cause autosomal dominant ataxia-pancytopenia syndrome with neurologic and hematologic manifestations, underscoring the importance of comprehensive genetic and functional testing in patients with unexplained ataxia and cytopenias.

References

• American Journal of Human Genetics • 2016 • Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L PMID:27259050
• BMC Neurology • 2019 • Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – a case report PMID:31053103
• Journal of the Peripheral Nervous System • 2020 • Ataxia pancytopenia syndrome due to SAMD9L mutation presenting as demyelinating neuropathy. PMID:32808377
• The Journal of Experimental Medicine • 2021 • Germline SAMD9L truncation variants trigger global translational repression. PMID:33724365
• Proceedings of the National Academy of Sciences of the United States of America • 2021 • SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression. PMID:34417303
• Cancer Cell • 2013 • Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. PMID:24029230
• Genes • 2022 • Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy. PMID:36553623

Evidence Based Scoring (AI generated)