De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic RECQL4 variants

Abstract

Rothmund-Thomson syndrome (RTS) is a rare autosomal-recessive disorder with clinical features consisting of rash, poikiloderma, sparse hair, short stature, juvenile cataracts, skeletal abnormalities, and cancer predisposition. Genetic studies involving detection of pathogenicRECQL4variants provide the diagnostic certitude. Osteosarcoma was found in two-thirdsRECQL4-mutated RTS patients, while hematological malignancies were rarely reported. The variant diversity ofRECQL4gene has not been fully identified and mutations associated with hematologic malignancies are not well described. In this study, we presented a pedigree of RTS from a Chinese family, among which the proband was diagnosed with de novo myelodysplastic syndrome (MDS). Comprehensive medical examination and chromosome karyotyping were performed on the proband. Whole exome sequencing (WES) was performed on the proband, his sister and his mother. The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction–based Sanger sequencing. Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity. Three novelRECQL4germline variants, including c.T274C, c.G3014A, and c.G801C, were identified by WES and validated by Sanger sequencing. Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants. The co-occurringU2AF1p.S34F andTP53p.Y220C mutations might contribute to the development of MDS. Our study expands the mutational spectrum ofRECQL4and provides underlying molecular mechanism for the development of MDS in RTS patients.