RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium

Noncompaction of the ventricular myocardium(NVM),the third most diagnosed cardiomyopathy,is characterized by prominent trabeculae and intratrabecular recesses.However,the genetic etiology of 40%–60%of NVM cases remains unknown.Here,we identify two infants with NVM,in a nonconsanguineous family,with a typical clinical presentation of persistent bradycardia since the prenatal period.A homozygous missense variant(R223L)of RCAN family member 3(RCAN3)is detected in both infants using whole-exome sequencing.In the zebrafish model,marked cardiac dysfunction is detected in rcan3 deficiency(MO-rcan3^(ATG)-injected)and rcan^(−/−) embryos.Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos.RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout;however,hRCAN3 mRNAs rescue these phenotypes.RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model.In human cardiomyocytes,RCAN3 deficiency results in reduced proliferation and increased apoptosis,together with an abnormal mitochondrial ultrastructure.Thus,we suggest that RCAN3 is a susceptibility gene for cardiomyopathies,especially NVM and that the R223L mutation is a potential loss-of-function variant.

Whole exome sequencing revealed a heterozygous elongation factor Tu GTP-binding domain containing 2(EFTUD2)mutation in a couple experiencing recurrent pregnancy loss

To the Editor:Recurrent pregnancy loss(RPL)is defined as the failure of two or more clinically recognized pregnancies.[1]Both parental and embryonic/fetal factors are associated with RPL.Parental factors include balanced chromosome rearrangements,maternal antiphospholipid syndrome,uterine anomalies,and hormonal or metabolic disorders.[2]Of the examined products of conception(POC),approximately 60%of early pregnancy losses result from sporadic chromosomal abnormalities in embryos,specifically numeric chromosome errors.However,up to 50%of RPL cases remain unexplainable by known causes.Here,we report a couple who have experienced four consecutive clinical pregnancy losses within 10 weeks of gestation,and describe a novel(elongation factor Tu GTP-binding domain containing 2[EFTUD2],Online Mendelian Inheritance in Man[MIM]#603892)nonsense mutation(c.1012G>T,p.E338∗)found in embryonic tissues from each of the last three miscarriages by whole exome sequencing(WES)analysis.In addition,we generated a zebrafish line with a mutation homologous to the human EFTUD2 disruption to investigate the relationship between this mutation and RPL.We hypothesized that the mutation was associated with embryonic lethality,which may induce RPL in patients.The study was approved by the Medical Ethics Committee of the West China Second University Hospital,Sichuan University,China(No.2016[029]).Written informed consent was obtained from the couple before genetic testing.