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.

Novel compound heterozygous variants in lectin mannose-binding 2-like gene identified in a Chinese autosomal recessive mental retardation-52(MRT52)patient with phenotype expansion

To the Editor:Autosomal recessive mental retardation-52(MRT52,OMIM:616887)was first reported in 2016 and is characterized by global developmental delay,[1]severe intellectual disability(ID),speech disorder,and seizures,but no dysmorphic features.[1,2]MRT52 is caused by a homozygous mutation in the vesicular integral membrane protein 36 kDa(VIP36)-like protein,which is also named lectin mannose-binding 2-like(LMAN2L)gene(OMIM:609552).[3]Nufer et al[4]mapped the LMAN2L gene to chromosome 2q11.2.Although the exact LMAN2L function is not clear,evidence suggests that the LMAN2L gene encodes a transmembrane protein(TM)located in the endoplasmic reticulum(ER).