Dentate nucleus hyperintensities as a clue to diagnosis in SAMD9L-related ataxia with gain-of-function variants

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28 Oct 2026 0 comments

Ataxia pancytopenia syndrome (ATXPC) is a rare autosomal dominant disorder caused by heterozygous germline gain-of-function (GoF) pathogenic variants in the tumour suppressor gene sterile alpha motif domain containing 9 like (SAMD9L).1 From its first description in 1978 to the confirmation of SAMD9L pathogenicity in 2016 (), more than 120 individuals from more than 40 families have been reported ().1–3 ATXPC is characterised by neurologic and haematologic features, most notably progressive cerebellar ataxia, peripheral neuropathy and cytopenias with a predisposition to bone marrow failure, monosomy 7 and myeloid malignancies ().1–3 The haematological phenotype is modulated by the occurrence of somatic genetic rescue (SGR) events in haematopoietic cells, which provides a selective advantage through elimination or inactivation of the pathogenic germline allele. Mechanisms by which SGR can occur include secondary loss-of-function (LoF) variants affecting the mutated allele,...