Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Abstract

Sterile alpha motif domain protein 9 (SAMD9) and its paralogue SAMD9-like (SAMD9L) are cytoplasmic proteins encoded by two juxtaposed single-exon genes on chromosome 7q21. They share a 60% amino acid sequence identity and likely originated from a duplication of a common ancestral gene 1 . Their function remains enigmatic; they have been linked to tumor suppression 2 , inflammation 3 , stress response 4 , development 4 , endosomal fusion 5,6 and protein translation 7,8 . Both proteins were also shown to function as restriction factors forming a cross-species barrier for poxvirus infection [9][10][11][12] . Structural analysis of these large proteins has been limited to homology modeling, which predicted identical domains in either protein (SAM, ALBA2, SIR2, P-loop/ NTPase and OB-fold) 13 . Moreover, these genes exhibit tight regulation during embryonic development and transition to ubiquitous expression levels in adult tissues 14,15 .Notably, Samd9l-haploinsufficient mice develop myeloid neoplasia mimicking human MDS with monosomy 7 5 . Several groups reported germline SAMD9 or SAMD9L mutations (SAMD9/9L mut ) underlying new human syndromes with a propensity for cytopenia, bone marrow failure (BMF) and MDS with non-random monosomy 7 or deletion of 7q 6,16-28 . SAMD9 mutations (SAMD9 mut ) were initially linked to a fatal, early-onset MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) 6,29 . In contrast, SAMD9L mutations (SAMD9L mut ) were originally described in families with a progressive neurological phenotype, multi-lineage cytopenia and bone marrow hypoplasia (ataxia-pancytopenia syndrome) 16,17 . Recent reports broadened this spectrum and found missense SAMD9/9L mut in non-syndromic familial MDS [30][31][32][33] , truncating SAMD9L mut in children with autoinflammatory panniculitis resembling CANDLE

Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue

“… 43-49 The novelty of our finding lies in the identification of somatic rescue arising in response to a GOF RPA1 E240K mutation, a known phenomenon described in patients with GOF mutations in SAMD9/SAMD9L genes. 34,50-52 We also observed improvement of oral leukoplakia in P1 over time. One can speculate that mucosal tissue in this patient also underwent somatic reversion, given that somatic mosaicism has been recently shown to be common in healthy human tissues.…”

“…Single-cell DNA sequencing of BM cells was performed by using a custom targeted panel on the Tapestri Platform (Mission Bio). Briefly, a set of amplicons including RPA1 variants found in P1 (germline c.718G>A, chr17:1782314:G>A and somatic c.1735G>T, chr17:1798378:G>T) were amplified as previously reported 34 and outlined in detail in the supplemental Methods (available on the Blood Web site). In addition, we used oligonucleotide-conjugated antibodies targeting CD3, CD11b, CD19, CD34, CD38, CD45RA, and CD90 cell surface proteins.…”

Reversion Mosaicism in Primary Immunodeficiency Diseases

“…Germline mutations in sterile alpha motif domain protein 9 ( SAMD9 ) and its paralogue SAMD9-like ( SAMD9L ), which are located in tandem on chromosome 7q21, are associated with human syndrome with a propensity for bone marrow failure and myelodysplastic syndrome (MDS) with monosomy 7 and 7q deletion ( 100 , 101 ). SAMD9 and SAMD9L gain-of-function mutations represent a strong growth-suppressive effect because of the defective endosomal turnover of cytokine receptors such as the epidermal growth factor receptor ( 100 ).…”

“…In the recent investigation of pediatric MDS cohort, 8% of the consecutively diagnosed patients harbored germline SAMD9 / SAMD9L mutations ( 101 ). Of the patients with SAMD9 / SAMD9L mutations, 61% underwent somatic reversion, of whom 51% had benign (CN-LOH or second-site mutation) and 95% had maladaptive nature (monosomy 7 and 7q deletion).…”

Convergence of specified RUNX2, SALL1, and SAMD9 variants permits normal global immune and endocrine function despite bone marrow hypocellularity and reduced ovarian reserve

“…Most SAMD9 variants presage early death from myeloid dysplasia, immune system imbalance, adrenal insu ciency, or chronic undernourishment from feeding di culty [18]. SAMD9 mutations via germline transmission predispose to low platelets, acquired monosomy 7, constitutional abnormalities (e.g., ambiguous genitalia) and immune dysfunction [19]. Less is known about SAMD9 variants which appear as de novo events.…”