Background/Purpose: The Sterile Alpha Motif Domain Containing 9 Like protein that is encoded by SAMD9L plays a role in endosome fusion, and deletions (haploinsufficiency) of SAMD9L including loss of the chromosome 7 where SAMD9L is located (monosomy 7) have been associated with myelodysplasia in humans and mice. Recently missense mutations in SAMD9Lwere described in patients presenting with ataxia-pancytopenia syndrome. Here we describe 6 patients with de novoframeshift mutations in SAMD9L who present with early-onset systemic inflammation, variable interstitial lung disease and cytopenias.

Methods: Whole exome/genome sequencing (WES/WGS) on trios using Illumina HiSeq 2000 platform were performed. An interferon-response-gene score was assessed using a customized Nanostring assay. Toll-like receptor (TLR) stimulation assays, STAT phosphorylation assay and immunofluorescence staining were performed in patients and healthy controls (HCs), PBMCs, monocytes and T cells, and fibroblasts, respectively.

Results: We identified 6 patients with 4 de novo frameshift variants in SAMD9L. All 6 patients had disease onset between 1 and 7 days of life with generalized nodular skin rashes, fever and increased inflammatory markers (ESR and CRP). Skin biopsies from all 6 patients revealed a neutrophilic panniculitis. Four patients (67%) had developed severe interstitial lung disease (ILD) in infancy, all 4 developed pancytopenia, low B-cell count and hypogammaglobulinemia, and two of those underwent bone marrow transplant. The other 2 patients developed leukopenia, a low B cell count, hypogammaglobulinemia and recurrent pulmonary infiltrates at the age of 3 and 5 years, respectively. Additionally, brain imaging revealed basal ganglia calcifications and/or demyelinating changes in 4 out of the 6 patients.Tertiary structure modelling of SAMD9L protein predicted that the 4 variants lie in the p-loop containing the hydrolase domain (amino acids 692-946) of the molecule. qRT-PCR of healthy control cell subsets and tissues showed that SAMD9L mRNA relative expression is high in B and NK lymphocytes, moderate in T cells, monocytes, neutrophils, lung and muscle, and low in skin, liver, heart and kidney tissues. Analysis of each individual gene expression level by nanostring in comparison with healthy controls demonstrated significantly higher levels of the following IRGs: DDX60, EPSTI1, GBP1, IFI6, ISG15, LY6E, OAS1, OAS2, OAS3, RSAD2, RTP4and SOCS1.Stimulation of PBMCs with the TLR ligands poly I:C, ODN, and LPS induced a 200-fold increase in IFI27 and a 30-fold increase in IFNA1 and IFNB1 transcription compared to baseline. IF staining of patient fibroblasts showed a 1.5-fold increase in EEA1 early endosome formation and a 2.5-fold decrease in RAB5 late endosome formation compared to healthy fibroblasts. Patient had constitutive upregulation of STAT1 and STAT6 in monocytes and of STAT1 and STAT3 in T cells.

Conclusion: We describe a novel immunedysregulatory disease caused by de novotruncating variants in SAMD9L that presents similar to CANDLE with neutrophilic pannicultis and points to an important role of SAMD9L on regulation of adaptive and innate immune responses.

Acknowledgements: This work was supported by the NIH IRP of NIAID

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/truncating-mutations-in-samd9l-cause-an-early-onset-immune-dysregulatory-syndrome-of-neutrophilic-panniculitis-interstitial-lung-disease-and-cytopenias/