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Genetics for understanding the clinical features of Shwachman‐Diamond Syndrome

This issue of the journal includes a paper entitled “Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability”, which correlates genetic and clinical data in an autosomal recessive disorder (Valli et al, 2019). Many haematological disorders have a genetic basis. Genetic research plays an instrumental role in the discovery of new biological pathways underpinning complex human diseases and the evaluation of new targets for therapeutic development. Shwachman-Diamond syndrome (SDS; Online Mendelian Inheritance in Man number 260400) is a very rare autosomal recessive disease, with an estimated incidence of about 1:168 000 in Italy (Minelli et al, 2012). So, collecting data on 14 cases, as a result of a national collaboration, provides clinical and genetic data on a sample large enough to allow the authors to discuss relevant clinical data, such as those regarding prognosis. The somatic cytogenetic anomaly, namely the Interstitial deletion of the long arm of chromosome 20, del(20)(q), discussed in the paper, is one of the most frequent clonal chromosome anomalies acquired in bone marrow (BM) of SDS patients. The same group has also provided evidence regarding the differences between the del(20)(q) observed in myelodysplastic syndrome (MDS) and SDS (Valli et al, 2013). So, one message that we derive from the paper is the relevance of correlating cytogenetic and molecular data related to somatic changes to the type of disease in which they are found. It is of interest how the authors hypothesize that the BM cells of SDS patients “attempt to improve” their function, impaired by the defective SBDS protein, through the acquisition of somatic cytogenetic anomalies, such as del(20)(q) or through a copy number neutral loss of heterozygosity, and how they confirm that the del(20)(q) may imply a lower risk of developing MDS/acute myeloid leukaemia (AML), due to the loss of the EIF6 gene. These data are relevant in SDS syndrome and haematological diseases, by relating a cytogenetic anomaly with the significance of the loss of a single gene whose functions are part of the pathway of the disease-causing gene, SBDS. In general, Valli et al (2019) demonstrate that the detection of chromosomal abnormalities with specific effects on genes is also relevant in haematological disorders that are neither neoplastic (acute leukaemia) nor dysplastic. The authors have been able to demonstrate that del(20)(q) in SDS patients has good prognostic significance, not only regarding the risk to develop MDS/AML, but also regarding the presence/severity of some haematological symptoms, such as cytopenia and hypoplastic marrow. Haemoglobin concentration, neutrophil and platelet counts were higher in their SDS patients carrying del(20)(q) compared to 25 SDS patients without clonal del(20)(q). As we are dealing with a very rare disease, these data are of clear relevance in the clinical management of patients. Lindsley et al (2017) reported that some patients who developed MDS at a young age were identified as SDS only after the demonstration of molecular abnormalities identified by studying their BM as part of a routine molecular work-up for MDS. Thus, the knowledge that some changes (either cytogenetic or molecular) are as relevant for the identification of patients with haematological diseases as for patients suffering from a well-defined genetic disorder, will become a tool for the better care of patients in whom the phenotype is not immediately suggestive for the presence of a constitutional genetic disease. The data reported by Valli et al (2019) have a relevant practical impact on the clinical management of SDS patients. As SDS patients are often not identified as having a rare disease, but diagnosed as haematological patients, the demonstration of these specific cytogenetic and molecular changes will be useful to move from a haematological diagnosis to a diagnosis of a specific rare disease. The latter is essential for genetic counselling for the family, selecting BM donors among family members, in cases of worsening of Correspondence: Dr Lucia Nacci, Molecular Medicine, University of Pavia, Via Forlanini 14, Pavia 27100, Italy. E-mail: lucia.nacci01@universitadipavia.it editorial comment