A novel missense mutation outside the DNAJ domain of DNAJC21 is associated with Shwachman-Diamond syndrome

Shwachman-Diamond Syndrome (SDS) and related bone marrow failure disorders are characterized by early onset pancytopenia with a hypocellular bone marrow, short stature, and pancreatic insufficiency, along with an increased risk for myeloid malignancies. Recently, several cases with an SDS-like syndrome have been reported to harbor mutations in the DNAJ domain of DNAJC21. Here, we report an intriguing case of a 13.5 years-old female born to Turkish consanguineous parents with a novel missense mutation occurring outside the DNAJ domain of the DNAJC21 gene. Whole-exome and Sanger sequencing confirmation revealed a homozygous missense mutation in DNAJC21 gene c.463T>C, p.W155R which was considered as pathogenic in in silico analyses. Initially, this patient's vague and atypical symptoms led to uncertainty of the underlying diagnosis. Upon confirmation of the genetic mutation, a number of functional studies such as diepoxibutane test, proliferation test from peripheral blood mononuclear cells, and cytokinesis-block micronucleus cytome assay performed with the patient cells confirmed the likely diagnosis of an SDS-like syndrome attributable to DNAJC21 dysfunction. Through the analysis of this rare case, we illuminate the pleiotropic features of this unique bone marrow failure syndrome and emphasize the paramount role of genomic testing to discriminate a range of closely related bone marrow failure disorders.