ABSTRACT
Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
Subject(s)
Alleles , Heart Defects, Congenital , Heart Valve Diseases , Loss of Function Mutation , Phospholipase D , Female , Heart Defects, Congenital/enzymology , Heart Defects, Congenital/genetics , Heart Valve Diseases/enzymology , Heart Valve Diseases/genetics , Humans , Male , Phospholipase D/genetics , Phospholipase D/metabolismABSTRACT
OBJECTIVE: The aim of this study was to investigate whether fibroblast growth factor receptor 4 (FGFR4) could serve as a potential therapeutic target, prognostic biomarker or biomarker predicting radiotherapy sensitivity in oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC). METHODS: FGFR4 immunohistochemistry and FGFR4/CEN5q FISH were performed on tissue microarrays from 212 OSCC and 238 OPSCC patients. FGFR4 genotypes were determined by PCR and DNA sequencing in 76 random OPSCC samples. The response to radiotherapy was evaluated 3 months after the last radiotherapy treatment session by a head and neck radiation oncologist and/or surgeon during clinic visits. The results were correlated to overall survival and response to radiotherapy. RESULTS: The FGFR4 protein was overexpressed in 64% (153/238) of OPSCCs and 41% (87/212) of OSCCs. The FGFR4 gene was amplified in 0.47% (1/212) of OSCCs and 0.42% (1/238) of OPSCCs, and the FGFR4 Gly388Arg polymorphism was detected in 62% (47/76) of OPSCCs. FGFR4 protein expression, FGFR4 gene copy numbers and FGFR4 genotypes were not related to overall survival or response to radiotherapy in OSCC or OPSCC. CONCLUSION: FGFR4 is frequently overexpressed in OSCC and OPSCC in the absence of gene amplification, and may serve as a potential predictive marker for FGFR4-directed targeted therapy in OSCC and OPSCC.
Subject(s)
Carcinoma, Squamous Cell/genetics , Mouth Neoplasms/diagnosis , Mouth Neoplasms/genetics , Oropharyngeal Neoplasms/diagnosis , Oropharyngeal Neoplasms/genetics , Receptor, Fibroblast Growth Factor, Type 4/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/radiotherapy , Female , Genotype , Humans , Immunohistochemistry , Male , Middle Aged , Mouth Neoplasms/radiotherapy , Oropharyngeal Neoplasms/radiotherapy , Polymerase Chain Reaction , Polymorphism, Genetic , Prognosis , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Sequence Analysis, DNA , Tissue Array Analysis , Up-RegulationABSTRACT
Cases of unexplained intrauterine fetal death (IUFD) can be reduced by full placental examination, with or without autopsy. Determination of the umbilical coiling index (UCI) is considered to be a part of full placental examination. Umbilical hypercoiling (UCI above 0.30 coils/cm) is associated with IUFD. In a large retrospective study, we found an incidence of 18% umbilical hypercoiling in IUFD. We explored the association between umbilical hypercoiling and 2nd- and 3rd-trimester IUFD in 77 cases. There was a significant negative correlation between the UCI and gestational age of IUFD (P<0.001). More severe cases of hypercoiling were observed in the categories of IUFD at a younger age and with a longer duration. Signs of fetal thrombosis were significantly more present in IUFDs with umbilical hypercoiling. An umbilical cord stricture and hypercoiling seem to be significantly more common in IUFD. The severity of hypercoiling was of no influence on the presence or absence of an umbilical cord stricture. Furthermore, there was no significant difference in signs of cardiac failure between the groups of IUFD with and without umbilical hypercoiling. Our findings may be explained by the theory that hypercoiling leads to a disturbed fetal-placental circulation. Therefore, determination of the UCI should be part of the routine placental examination of cases of IUFD.
