Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3.

BACKGROUND: Biallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies. METHODS: Trio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype. RESULTS: A novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus. CONCLUSIONS: These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.

Thermoinduced Radical Cyclization for the Synthesis of Sultines.

A thermoinduced radical homolytic substitution cyclization of alkenyl tethered sulfinate esters was displayed under mild metal-free conditions, enabling the functionalization of alkenes and leading to structurally diverse value-added sultine products. The process utilizes readily available substrates using inexpensive 5% benzoyl peroxide (BPO) as an initiator to generate functionalized sultines with broad functional group tolerance in medium to excellent yields in a highly atom-economical manner. In addition, the obtained sultines could be further readily functionalized toward valuable sultone frameworks in one pot. A thermo-catalytic radical chain process was proposed based on mechanistic studies.

Genetic and prenatal diagnosis of a Chinese pedigree with pathogenic TOE1 variants causing pontocerebellar hypoplasia type 7.

Objective: Biallelic pathogenic variants in TOE1 cause pontocerebellar hypoplasia type 7 (PCH7), a rare neurological condition characterized by psychomotor retardation, spastic paraplegia, seizures, gonadal abnormalities and brain anomalies. Currently, only 14 postnatally diagnosed PCH7 patients have been described. However, the prenatal clinical profile of PCH7 has not yet been reported.Method: Whole-exome sequencing (WES) was performed to screen for causal variants.Results: We report the pedigree of a Chinese woman with two eventful pregnancies with fetuses that showed brain anomalies, including microcephaly, cerebral anomalies, enlarged ventricles, corpus callosum thinning, abnormal lateral fissure, underdeveloped insula and pons and brainstem hypoplasia. Interestingly, corpus callosum thinning was observed in fetus 1 but not in fetus 2. An abnormal lateral fissure and an underdeveloped insula were shown in fetus 2 but not fetus 1. Biallelic variants c.716T > C (p.Phe239Ser) and c.955C > T (p.His319Tyr) in TOE1 were identified in both fetuses.Conclusion: We first describe the prenatal features of a Chinese pedigree with PCH7 caused by biallelic pathogenic variants in TOE1, with phenotypic variability observed even within the same family. Novel phenotypes, an abnormal lateral fissure and an underdeveloped insula were observed in the fetus in our study. These findings will enrich our knowledge of the clinical characteristics, management and genetic counseling of PCH7.