Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141,DDHD2,and LHFPL5

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation.Here,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and deafness.Homozygosity mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,p.Trp90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,p.Leu84^(*))were identified.A Tmem141^(p.Trp90^(*)/p.Trp90^(*))mouse model was generated.Behavioral studies showed impairments in learning ability and motor coordination.Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells.Transmission electron microscopy showed abnormal mitochondrial morphology.Furthermore,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model.Conclusively,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in patient.Notably,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

Expression of Target Genes in Cumulus Cells Derived from Human Oocytes with and without Blastocyst Formation

Objective:The transcriptional profile of cumulus cells(CCs)during oocyte maturation provides information for predicting oocyte developmental competence.Our previous study using a mouse model indicated that there were nine different genes related to oocyte development potential expressed in CCs during oocyte maturation.The purpose of this study was to elucidate whether gene expression levels of CCs during oocyte maturation are associated with oocyte developmental competence.Methods:The human CCs collected from each oocyte were divided into two groups after tracking depending on whether or not they developed to the blastocyst stage:(1)the oocytes were developed to blastocyst stage after fertilization(B+)and(2)the oocytes were not developed to blastocyst stage after fertilization(B−).The expression levels of the nine selected genes(ARRB1,ATP2C1,CDH5,CNTNAP1,LGR4,MKLN1,RHOBTB1,SIX2,and SMC2)were examined.CCs were obtained from 29 women who were undergoing intracytoplasmic sperm injection treatment cycles.Quantitative reverse transcriptase-polymerase chain reaction analysis was performed on cumulus masses collected before insemination.Each sample was run three times.Statistically significant differences in mRNA expression of the target genes in independent samples were evaluated by two-tailed Student’s t-test,and P<0.05 was considered significantly different.Results:There were significant differences in the mRNA expression levels of ARRB1(P=0.016),LGR4(P=0.025),and SMC2(P=0.013)between the groups B+and B−.Gene expression of ARRB1,LGR4,and SMC2 in CCs is related to blastocyst development.Conclusions:Analysis of expression of ARRB1,LGR4,and SMC2 genes in CCs as biomarkers may provide predictive information on oocyte developmental competence before insemination and fertilization.

Diagnostic Guidelines for Infertility

Infertility seriously endangers the reproductive health of women at childbearing age.It is defined as the failure to achieve successful pregnancy after 1 year or more of regular unprotected intercourse.Broadly defined,infertility includes two aspects-failure to conceive or have a live birth.This guideline only addressed content relevant to the former.It was proposed by the gynecological endocrine group of the Chinese Society of Obstetrics and Gynecology,Chinese Medical Association,based on relevant guidelines of the World Health Organization,the American Society for Reproductive Medicine,the National Institute for Health and Clinical Excellence,as well as the clinical practice in China.The guideline was reviewed by experts and doctors from medical institutions at all levels,which is applicable to the diagnosis of infertility by physicians in obstetrics,gynecology,and andrology at various medical institutions nationwide.