Antonella Minelli, Assistant Professor, P.I.
Ibrahim Taha, PhD student in Translational Medicine
Shwachman-Diamond Syndrome (SDS, OMIM #260400) is a rare inherited bone marrow failure syndrome that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. It is inherited as autosomal recessive disease and its clinical aspects include also skeletal alterations and an increased risk for myelodysplasia and acute myeloid leukaemia. All clinical signs show wide variability and patients with mild phenotypes and late diagnosis are common.
The major disease gene is SBDS and 90% of individuals affected by SDS have biallelic pathogenic variants in SBDS. SBDS functions as a cofactor for elongation factor-like GTPase 1 (EFL1) in removing the anti-association factor eIF6 from the subunit joining face of the 60S ribosomal subunit in the final step of late cytoplasmic maturation.
More recently, WES studies revealed biallelic mutations in two novel genes, DNAJC21 and EFL1, while heterozygous dominant negative mutations in SRP54 were found in patients with SDS-like phenotype. This discovery has confirmed the genetic heterogeneity of SDS and, particularly, has supported the hypothesis that the primary defect in SDS is impaired maturation of the large ribosomal subunit. For this reason, SDS has included in a heterogeneous class of diseases known as ribosomopathies.
Current research activity is focused on the WES data obtained by a project, still in progress, previously funded by Associazione Italiana Sindrome di Shwachman.
We are analysing the WES data of a group of 16 SDS patients focusing on:
i) the search for variants in genes linked to the risk of haematological disorders;
ii) the evaluation of variants in uncertain genetic modifiers, that, if inherited as monogenic tracts in addition to SBDS pathogenic variants could produce the so-called dual molecular diagnosis;
iii) the evaluation of an eventual digenic inheritance by bioinformatic platforms to explain the SDS variable phenotype
In addition, recent relevant publications showed that EIF6 is the most commonly somatic mutated gene in SDS patients in which no evident myelodysplasia evolution were detected. Through exomes analysis, we identified a patient with a germinal mutation in this gene and this prompted us to start the sequencing of EIF6 in SDS cases of which the WES is not available.
Maserati E, Minelli A, Olivieri C, Bonvini L, Marchi A, Bozzola M, Danesino C, Scappaticci S, Pasquali F. Isochromosome (7)(q10) in Shwachman syndrome without MDS/AML and role of chromosome 7 anomalies in myeloproliferative disorders. Cancer Genet Cytogenet. 2000 Sep;121(2):167-71. doi: 10.1016/s0165-4608(00)00246-6. PMID: 11063802.
Minelli A, Nicolis E, Cannioto Z, Longoni D, Perobelli S, Pasquali F, Sainati L, Poli F, Cipolli M, Danesino C. Incidence of Shwachman-Diamond syndrome. Pediatr Blood Cancer. 2012 Dec 15;59(7):1334-5. doi: 10.1002/pbc.24260. PMID: 22887728.
Morini J, Babini G, Mariotti L, Baiocco G, Nacci L, Maccario C, Rößler U, Minelli A, Savio M, Gomolka M, Kulka U, Ottolenghi A, Danesino C. Radiosensitivity in lymphoblastoid cell lines derived from Shwachman-Diamond syndrome patients. Radiat Prot Dosimetry. 2015 Sep;166(1-4):95-100. doi: 10.1093/rpd/ncv152. PMID: 25870433.
Nacci L, Valli R, Maria Pinto R, Zecca M, Cipolli M, Morini J, Cesaro S, Boveri E, Rosti V, Corti P, Ambroni M, Pasquali F, Danesino C, Maserati E, Minelli A. Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene. Genes Chromosomes Cancer. 2017 Jan;56(1):51-58. doi: 10.1002/gcc.22401. PubMed PMID: 27553422.
Taha I, Foroni S, Valli R, Frattini A, Valli R, Roccia P, Porta G, Zecca M, Bergami E, Cipolli M, Pasquali F, Danesino C, Scotti C, Minelli A. Case Report: Heterozygous germline variant in 1 EIF6 additional to biallelic SBDS pathogenic variants in a patient with ribosomopathy Shwachman-Diamond Syndrome. Frontiers (in press)