Structural variation in SBDS gene, with loss of exon 3, in two Shwachman-Diamond patients

Minelli, Antonella; Nacci, Lucia; Valli, Roberto; Pietrocola, Giampiero; Ramenghi, Ugo; Locatelli, Franco; Brescia, Letizia Pomponia; Nicolis, Elena; Cipolli, Marco; Danesino, Cesare

doi:10.1016/j.bcmd.2016.06.007

Cited by 5 publications

(3 citation statements)

References 8 publications

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“…The other patient with a large deletion had a deletion of exon 3; deletions in this region have been previously reported. 45 , 46 Our findings suggest investigation for large structural variants in patients with a single known SBDS PV without a second pathogenic allele may be required in order to identify the genetic etiology of SDS.…”

Section: Discussion/conclusionmentioning

confidence: 89%

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

et al. 2022

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Background and Objectives Shwachman Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities. Methods We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute’s (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort. Results PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258+2T>C and c.183_184TA>CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies. Conclusions SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management.

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Section: Discussion/conclusionmentioning

confidence: 89%

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

et al. 2022

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“…Compound heterozygosity of c.258+2T>C with c.258+374_459+250del (p.Ile87_Gln153del) was detected in a patient presenting with severe anemia, cyclic neutropenia, pancreatic exocrine insufficiency and skeletal abnormalities [ 46 ]. SBDS: c.[258+533_459+403del];[258+2T>C], a deletion encompassing exon 3, is a recurrent deletion reported in patients with variable clinical presentations of SDS [ 47 ]. Of interest, the variant was characterized as a “founder”, one originating independently twice in two different geographical places in Italy (Sicily and Lazio) as a result of gene conversion and non-homologous allelic recombination between SBDS and its pseudogene, SBDSP [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

“… Prosite graphic presentation of the SBDS gene and some of the missense variants recorded in cases with typical or atypical presentations of Shwachman Diamond Syndrome. Selected variants include those reported in ClinVar and LOVD as pathogenic or likely pathogenic and are in black; variants in red are the ones detected in the present family; blue lines represent large deletions described in the literature [ 45 , 46 , 47 ]. …”

Section: Figurementioning

confidence: 99%

Lethal Complications and Complex Genotypes in Shwachman Diamond Syndrome: Report of a Family with Recurrent Neonatal Deaths and a Case-Based Brief Review of the Literature

Veltra,

Marinakis,

Kotsios

et al. 2024

Children

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Shwachman Diamond Syndrome (SDS) is a multi-system disease characterized by exocrine pancreatic insufficiency with malabsorption, infantile neutropenia and aplastic anemia. Life-threatening complications include progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), critical deep-tissue infections and asphyxiating thoracic dystrophy. In most patients, SDS results from biallelic pathogenic variants in the SBDS gene, different combinations of which contribute to heterogenous clinical presentations. Null variants are not well tolerated, supporting the theory that the loss of SBDS expression is likely lethal in both mice and humans. A novel complex genotype (SBDS:c.[242C>G;258+2T>C];[460-1G>A]/WFS1:c.[2327A>T];[1371G>T]) was detected in a family with recurrent neonatal deaths. A female neonate died three hours after birth with hemolytic anemia, and a male neonate with severe anemia, thrombocytopenia and neutropenia succumbed on day 40 after Staphylococcus epidermidis infection. A subsequent review of the literature focused on fatal complications, complex SBDS genotypes and/or unusual clinical presentations and disclosed rare cases, of which some had unexpected combinations of genetic and clinical findings. The impact of pathogenic variants and associated phenotypes is discussed in the context of data sharing towards expanding scientific expert networks, consolidating knowledge and advancing an understanding of novel underlying genotypes and complex phenotypes, facilitating informed clinical decisions and disease management.

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The pathogenic variant c.258+533_459+403del in SBDS gene is the commonest rare variant in Italy and shows a founder effect

et al. 2023

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Structural variation in SBDS gene, with loss of exon 3, in two Shwachman-Diamond patients

Cited by 5 publications

References 8 publications

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

Lethal Complications and Complex Genotypes in Shwachman Diamond Syndrome: Report of a Family with Recurrent Neonatal Deaths and a Case-Based Brief Review of the Literature

The pathogenic variant c.258+533_459+403del in SBDS gene is the commonest rare variant in Italy and shows a founder effect

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