From a novel pathogenic SAMD9L variant to cohort-wide insights: Whole-genome sequencing highlights somatic genetic rescue and phenotypic heterogeneity.

Germline gain-of-function variants in sterile alpha motif domain-containing 9-like (SAMD9L), located on chromosome 7q, cause a multisystem disorder characterized by bone marrow failure, immunodeficiency and variable neurological involvement. Disease evolution is frequently shaped by somatic genetic rescue (SGR), most commonly through monosomy 7, somatic loss-of-function (LOF) variants in cis or uniparental disomy of 7q (UPD7q). We report a 6-month-old girl presenting with pancytopenia and severe infections, in whom we identified a novel heterozygous SAMD9L variant. Trio-based whole-genome sequencing demonstrated maternal transmission and revealed distinct SGR mechanisms in both the proband and her asymptomatic mother, including UPD7q and an additional somatic LOF variant. Longitudinal molecular follow-up showed dynamic clonal evolution associated with haematological improvement. To assess the broader relevance of SAMD9/SAMD9L variants, we also performed a gene-centred analysis of the 2025 French Genomic Medicine Initiative (PFMG2025), enabling the identification and classification of additional candidate variants. These findings support systematic screening for SGR, including mosaic UPD7q, even in cases with apparently normal variant allele frequency, and highlight the importance of integrating haematopoietic and non-haematopoietic tissues in diagnostic workflows for inherited bone marrow failure syndromes.