Chromosomal translocation disrupting the SMAD4 gene resulting in the combined phenotype of Juvenile polyposis syndrome and Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Patients with germline variants in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT): JP-HHT syndrome. Next-Generation Sequencing (NGS) techniques disclose causative sequence variants in around 90% of HHT patients fulfilling the Curaçao criteria. Here we report a translocation event involving SMAD4 resulting in JP-HHT. METHODS: A patient fulfilling the Curaçao criteria was analyzed for variants in ENG, ACVRL1, and SMAD4 using standard techniques. Whole-genome sequencing (WGS) using both short-read NGS technology and long-read Oxford Nanopore technology was performed to define the structural variant and exact breakpoints. RESULTS: No pathogenic variant was detected in ENG, ACVRL1, or SMAD4 in DNA extracted from blood. Due to abortus habitualis, the proband´s daughter was submitted for chromosomal analysis, and a cytogenetically balanced chromosomal reciprocal translocation t(1;18)(p36.1;q21.1) was detected in the daughter and the patient. The balanced translocation segregated with both gastrointestinal cancer and HHT in the family. WGS provided the exact breakpoints of the reciprocal translocation proving disruption of the SMAD4 gene. DISCUSSION: A disease-causing reciprocal translocation between chromosome 1 and 18 with a breakpoint in the SMAD4 locus co-segregated with JP-HHT in an extended family. This observation warrants further analysis for chromosomal rearrangements in individuals with clinical HHT or JP-HHT of unknown cause.

Neonatal epicardial-derived progenitors aquire myogenic traits in skeletal muscle, but not cardiac muscle.

BACKGROUND/OBJECTIVES: Epicardium-derived progenitor cells (EPDCs) differentiate into all heart cell types in the embryonic heart, yet their differentiation into cardiomyocytes in the adult heart is limited and poorly described. This may be due to EPDCs lacking myogenic potential or the inert adult heart missing regenerative signals essential for directed differentiation of EPDCs. Herein, we aimed to evaluate the myogenic potential of neonatal EPDCs in adult and neonatal mouse myocardium, as well as in skeletal muscle. The two latter tissues have an intrinsic capability to develop and regenerate, in contrast to the adult heart. METHODS: Highly purified mouse EPDCs were transplanted into damaged neonatal and adult myocardium as well as regenerating skeletal muscle. Co-cultures with skeletal myoblasts were used to distinguish fusion independent myogenic conversion. RESULTS: No donor EPDC-derived cardiomyocytes were observed in hearts. In contrast, a remarkable contribution of EPDCs to skeletal muscle myofiber formation was evident in vivo. Furthermore, co-cultures of EPDCs with myoblasts showed that EPDCs became part of multinucleated fibers and appeared to acquire myogenic traits independent of a fusion event. Fluorescence activated cell sorting of EPDCs co-cultured with and without myoblasts and subsequent qRT-PCR of 64 transcripts established that the myogenic phenotype conversion was accomplished through induction of a transcriptional myogenic program. CONCLUSION: These results suggest that EPDCs may be more myogenic than previously anticipated. But, the heart may lack factors for induction of myogenesis of EPDCs, a scenario that should be taken into consideration when aiming for repair of damaged myocardium by stem cell transplantation.