Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants

Abstract

Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.

Figure 1.

Schematic of human DNAJC21, SRP54, and EFL1 showing position of disease-associated variants. Lollipop plot indicating the locations of variants in the DNAJC21, SRP54, and EFL1 genes. An unknown variant which resulted in loss of protein expression in a case with EFL1 was not included. Protein domains and structures were obtained from Pfam and Uniprot databases.

Figure 2.

Components of the Shwachman-Diamond syndrome pathway participate in ribosomal biosynthesis and initial escort by the signal recognition particle. Ribosome maturation begins in the nucleus with the formation of the pre-60S and pre-40S subunits. These subunits traffic through the nuclear pores to the cytosol where the final steps of ribosome maturation occur, forming the 80S ready for translation of mRNA into a nascent polypeptide. The polypeptide emerges from the ribosome and is further processed via the signal recognition particle. See text for further details.