Parental origin of the deletion del(20q) in Shwachman‐Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene

Abstract

Shwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal, and hematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20q) being the most frequent ones. We collected 6 SDS cases with del(20q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the hematological phenotype. By comparing hematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20q) in BM, we observed a significant difference for Hb levels (P < 0.012), and a difference slightly above the significance level for RBC counts (P < 0.053): in both cases the values were higher in patients with del(20q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. © 2016 Wiley Periodicals, Inc.

Shwachman‐Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability

“…SNP-array genotyping was performed on 14 SDS patients (Tables I and SI with raw data). Copy number variation analysis confirmed the presence of i(7)(q10) and del(20)(q), already identified by chromosome analyses and a-CGH (Maserati et al, 2009;Pressato et al, 2010;Nacci et al, 2017) (Table III). Interestingly, cnLOH regions involving the long arm of chromosome 20 were detected in three patients, namely UPN 1, 40 and 54.…”

“…The imprinted genes L3MBTL1 and SGK2 are expressed normally only if paternal in origin, thus suggesting possible differences in the BM status among SDS patients with either maternal (UPN 14, 20, 65, and 68) or paternal (UPN 1, 6, 13, 17, and 84) deleted chromosome. Considering the 12 available informative patients altogether, including those already reported (Nacci et al, 2017), the deleted chromosome 20 was of paternal origin in five cases and maternal (Table IV). So, no preferential parental origin of the deleted chromosome 20 was detected, and, therefore, the expression of these genes may be hardly relevant to the haematological phenotype of the patients with the del(20)(q).…”

“…The parental origin of the deleted chromosome 20 was determined by microsatellite analysis, as described by Nacci et al (), on the same DNA used for a‐CGH. The short tandem repeat (STRs) polymorphisms used were chosen based on their heterozygosity (always above 80%): D20S484, D20S195, D20S890, D20S601, D20S847, D20S884, D20S891.…”

“…The genes L3MBTL1 and SGK2 are located in a cluster of imprinted genes on chromosome 20, and their loss might be related to dysregulation of erythropoiesis and megakaryopoiesis (Aziz et al , ). In six patients with del(20)(q) (five of which were included in our aforementioned a‐CGH analysis), a possible preferential parental origin of the deleted chromosome 20 was excluded (Nacci et al , ). However, the authors noted that the haemoglobin concentration (Hb) and red blood cell count were higher in their SDS patients carrying del(20)(q) in comparison with 20 SDS patients without clonal del(20)(q) (Nacci et al , ).…”

The frequent and clinically benign anomalies of chromosomes 7 and 20 in Shwachman-diamond syndrome may be subject to further clonal variations

“…The del(20)(q) results in deletion of the EIF6 gene [11,12]. Both these anomalies are predicted to result in more efficient ribosome biogenesis in the BM abnormal clone which may lower the risk of MDS/AML [10,11] and result in a milder haematological condition compared to SDS patients with other chromosome changes or with normal karyotype [13][14][15]. These conclusions were further supported by a recent paper concerning the benign effects of somatic mutations of EIF6 [16].…”