Contributions
Abstract: S1580
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:00 - 08:15
Location: Room A8
Background
SAMD9L and SAMD9 are two genes located at chromosome 7q21 that encode for two large homologous proteins implicated in inflammatory and antiviral responses. While these genes can be lost somatically in myelodysplastic syndromes (MDS) (Nagamachi, Cancer Cell 2013), germline activating mutations have been recently associated to the autosomal dominant syndromes Ataxia-Pancytopenia (SAMD9L gene; Chen, Am J Hum Genet 2016) and MIRAGE (SAMD9 gene; MDS, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; Narumi, Nat Genet 2016). We and other have found that SAMD9 and SAMD9L germline heterozygous mutations further defined a spectrum of bone marrow failure (BMF) and MDS genetic predisposition in children (Tesi, Blood 2017; Bluteau, Blood 2017; Schwartz, Nat com 2017).
Aims
In order to delineate better the SAMD9/SAMD9L associated disorder, we analyzed a cohort of 22 patients (pts) with germline SAMD9 or SAMD9L mutations originating from 16 families.
Methods
Patients and relatives were originally investigated in the laboratory of the French Aplasia Center to search for a familial origin to their BMF or MDS. All subjects gave informed consent for genetic investigation, tissue banking and research, and this study was IRB approved. We here report the natural clinical history of 22 patients, with a median FU of 6 years (7 months-37y). In 14 of them, we analysed hematopoietic somatic events using WES and Sanger re-sequencing on blood or bone marrow samples, in comparison with fibroblast DNA.
Results
Fifteen and 7 pts with SAMD9L and SAMD9 germline mutations were identified, from 9 and 7 unrelated families, with a median age at first hematological signs of 13 months (8 months-46y) and 7 years (2-21y), respectively. Six out of 15 SAMD9L pts had neurological signs and 1/7 SAMD9 pts had a MIRAGE syndrome. Immunoglobulin deficiency with recurrent infections was found in both SAMD9 (N=4/7) and in SAMD9L (N=3/15) pts. Regarding hematological features, 20 pts had central cytopenia, with BM dysplasia in 11 and monosomy 7 in 10. Except one with an additional TERC germline mutation, patients did not present excess of blasts or cytogenetic lesion in addition to monosomy 7 at any point of their natural history. Ten had a family history while 12 presented simplex. Strikingly, spontaneous improvement in blood cell counts was seen in 11 pts, and MDS and monosomy 7 disappearance in 5 pts, with a median follow-up of 4 y. HSCT that was planned for five of these pts was eventually cancelled and they are still alive without consistent cytopenia with a follow-up of four to 33 years. Finally, two carrier subjects had no overt hematological signs. We sequenced blood and/or marrow mononuclear cells in 14 pts and found somatic changes such as acquired 7q uniparental disomy (UPD) or additional SAMD9 or SAMD9L cis-mutations in 7 of them, suggesting spontaneous genetic correction of the germline mutated allele.
Conclusion
Germline mutations of SAMD9 and SAMD9L delineate an inherited BMF/MDS predisposition disorder in children and young adults with frequent transient monosomy 7. Patients may benefit from a careful watch-and-wait policy rather than upfront HSCT, even when presenting with dysplasia and monosomy 7, a practice-changing option that will have to be carefully evaluated.
Session topic: 11. Bone marrow failure syndromes incl. PNH – Biology & Translational Research
Keyword(s): Bone Marrow Failure, MDS
Abstract: S1580
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:00 - 08:15
Location: Room A8
Background
SAMD9L and SAMD9 are two genes located at chromosome 7q21 that encode for two large homologous proteins implicated in inflammatory and antiviral responses. While these genes can be lost somatically in myelodysplastic syndromes (MDS) (Nagamachi, Cancer Cell 2013), germline activating mutations have been recently associated to the autosomal dominant syndromes Ataxia-Pancytopenia (SAMD9L gene; Chen, Am J Hum Genet 2016) and MIRAGE (SAMD9 gene; MDS, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; Narumi, Nat Genet 2016). We and other have found that SAMD9 and SAMD9L germline heterozygous mutations further defined a spectrum of bone marrow failure (BMF) and MDS genetic predisposition in children (Tesi, Blood 2017; Bluteau, Blood 2017; Schwartz, Nat com 2017).
Aims
In order to delineate better the SAMD9/SAMD9L associated disorder, we analyzed a cohort of 22 patients (pts) with germline SAMD9 or SAMD9L mutations originating from 16 families.
Methods
Patients and relatives were originally investigated in the laboratory of the French Aplasia Center to search for a familial origin to their BMF or MDS. All subjects gave informed consent for genetic investigation, tissue banking and research, and this study was IRB approved. We here report the natural clinical history of 22 patients, with a median FU of 6 years (7 months-37y). In 14 of them, we analysed hematopoietic somatic events using WES and Sanger re-sequencing on blood or bone marrow samples, in comparison with fibroblast DNA.
Results
Fifteen and 7 pts with SAMD9L and SAMD9 germline mutations were identified, from 9 and 7 unrelated families, with a median age at first hematological signs of 13 months (8 months-46y) and 7 years (2-21y), respectively. Six out of 15 SAMD9L pts had neurological signs and 1/7 SAMD9 pts had a MIRAGE syndrome. Immunoglobulin deficiency with recurrent infections was found in both SAMD9 (N=4/7) and in SAMD9L (N=3/15) pts. Regarding hematological features, 20 pts had central cytopenia, with BM dysplasia in 11 and monosomy 7 in 10. Except one with an additional TERC germline mutation, patients did not present excess of blasts or cytogenetic lesion in addition to monosomy 7 at any point of their natural history. Ten had a family history while 12 presented simplex. Strikingly, spontaneous improvement in blood cell counts was seen in 11 pts, and MDS and monosomy 7 disappearance in 5 pts, with a median follow-up of 4 y. HSCT that was planned for five of these pts was eventually cancelled and they are still alive without consistent cytopenia with a follow-up of four to 33 years. Finally, two carrier subjects had no overt hematological signs. We sequenced blood and/or marrow mononuclear cells in 14 pts and found somatic changes such as acquired 7q uniparental disomy (UPD) or additional SAMD9 or SAMD9L cis-mutations in 7 of them, suggesting spontaneous genetic correction of the germline mutated allele.
Conclusion
Germline mutations of SAMD9 and SAMD9L delineate an inherited BMF/MDS predisposition disorder in children and young adults with frequent transient monosomy 7. Patients may benefit from a careful watch-and-wait policy rather than upfront HSCT, even when presenting with dysplasia and monosomy 7, a practice-changing option that will have to be carefully evaluated.
Session topic: 11. Bone marrow failure syndromes incl. PNH – Biology & Translational Research
Keyword(s): Bone Marrow Failure, MDS