Objectives To explore the contribution of single‐gene defects to the genetic cause of cardiac left‐sided lesions (LSLs), and to evaluate the incremental diagnostic yield of whole‐exome sequencing (WES) for single‐gene defects in fetuses with LSLs without aneuploidy or a pathogenic copy‐number variant (pCNV). Methods Between 10 April 2015 and 30 October 2018, we recruited 80 pregnant women diagnosed with a LSL who had termination of pregnancy and genetic testing. Eligible LSLs were aortic valve atresia or stenosis, coarctation of the aorta, mitral atresia or stenosis and hypoplastic left heart syndrome (HLHS). CNV sequencing (CNV‐seq) and WES were performed sequentially on specimens from these fetuses and their parents. CNV‐seq was used to identify aneuploidies and pCNVs, while WES was used to identify diagnostic genetic variants in cases without aneuploidy or pCNV. Results Of 80 pregnancies included in the study, 27 (33.8%) had a genetic diagnosis. CNV‐seq analysis identified six (7.5%) fetuses with aneuploidy and eight (10.0%) with pCNVs. WES analysis of the remaining 66 cases revealed diagnostic genetic variants in 13 (19.7%) cases, indicating that the diagnostic yield of WES for the entire cohort was 16.3% (13/80). KMT2D was the most frequently mutated gene (7/66 (10.6%)) in fetuses with LSL without aneuploidy or pCNVs, followed by NOTCH1 (4/66 (6.1%)). HLHS was the most prevalent cardiac phenotype (4/7) in cases with a KMT2D mutation in this cohort. An additional six (9.1%) cases were found to have potentially deleterious variants in candidate genes. Conclusions Single‐gene defects contribute substantially to the genetic etiology of fetal LSLs. KMT2D mutations accounted for approximately 10% of LSLs in our fetal cohort. WES has the potential to provide genetic diagnoses in fetuses with LSLs without aneuploidy or pCNVs. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

No significant difference was noted between single cardiac tumours and multiple tumours regarding the degree of fetal heart damage. Cardiac rhabdomyoma is the most common cardiac tumour in fetus. The correlation between cardiac rhabdomyoma and TSC is high regardless of the presence of single or multiple tumours. This article is protected by copyright. All rights reserved.

Mutations in the gene encoding isocitrate dehydrogenase (IDH) have been identified in approximately 65-90 % of low-grade gliomas (LGGs). Various studies examining the relationship between IDH mutation with the clinical outcome in patients with LGGs have yielded inconclusive results. The purpose of the present meta-analysis of literature is to determine this effect. We conducted a meta-analysis of 10 studies (937 patients) that evaluated the correlation between IDH mutation and overall survival (OS). For the quantitative aggregation of the survival results, the IDH mutation effect was measured by hazard ratio (HR). Overall, the pooled HR was 0.585 (95 % CI, 0.376-0.911, p = 0.025, random effect model) for patients with IDH mutation vs patients without IDH mutation. IDH mutation was associated with better overall survival of LGGs. At least this trend was observed in our analysis.

Background: Marfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin-1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype-phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome. Methods: Genotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining. Results: A total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations. Conclusion: This study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients. K E Y W O R D Saortic aneurysm, aortic dissection, FBN1, Marfan syndrome

Objectives: Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM.Methods: We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigated for gestational age at diagnosis, gender, left or biventricular involvement, associated cardiac phenotypes, outcomes, and genetic testing data.Results: We identified 37 fetuses with NCCM out of 49,898 fetuses, indicating that the incidence of NCCM in the fetal population was 0.07%. Of the 37 fetuses, 26 were male, ten were female and one was of unknown gender. NCCM involvement biventricle is the most common (n = 16, 43%), followed by confined to the left ventricle (n = 14, 38%). Nineteen (51%) had additional congenital heart defects, with right-sided lesions being the most common (n = 14, 74%), followed by ventricular septal defects (n = 10, 53%). Hydrops fetalis was present in 12 cases (32%), of which four were atypical (pericardial effusion only). Sequencing analysis was performed at autopsy (n = 19) or postnatally (n = 1) on 20 fetuses. Of the 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, nine (47%) had positive genetic results, including one with a pathogenic copy number variant and eight with pathogenic/likely pathogenic variants. Non-sarcomere gene mutations accounted for the vast majority (n = 7). In contrast, sarcomere gene mutations occurred in only one case (TPM1), and no mutations were identified in the three most common sarcomere genes (MYH7, TTN, and MYBPC3) of pediatric and adult patients. Pathogenic/likely pathogenic variants were significantly more frequent in fetuses with congenital heart defects than those without congenital heart defects.Conclusions: Our data demonstrate that fetal NCCM is a unique entity. Compared with pediatric and adult NCCM, fetal NCCM is more prone to biventricle involvement, more likely to be complicated with congenital heart defects, and has a distinct genetic spectrum.

Background The NONO gene is located on chromosome Xq13.1 and encodes a nuclear protein involved in RNA synthesis, transcriptional regulation, and DNA repair. Hemizygous variants in NONO have been reported to cause mental retardation, X-linked, syndromic 34 (MRXS34) in males. Due to the scarcity of clinical reports, the clinical characteristics and mutation spectrum of NONO-related disorder have not been entirely determined. Methods We reported a fetus with hypoplastic left heart syndrome, performed a comprehensive genotyping examination, including copy-number variation sequencing and whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted deleterious effects of an intronic variant of NONO. Results Exome sequencing identified a novel intronic variant (c.154 + 9A > G) in intron 4 of the NONO gene (NM_001145408.1). It was predicted to insert 4 bp of intron 4 into the mature mRNA. Minigene assay revealed that the c.154 + 9A > G variant caused the activation of the intronic cryptic splice site and 4 bp insertion (c.154_155ins GTGT) in mature mRNA. Literature review shows that cardiac phenotype, including left ventricular non-compaction cardiomyopathy and congenital heart disease, are consistent features of MRXS34. Conclusion This study enlarges the mutation spectrum of NONO, further expands hypoplastic left heart syndrome to the phenotype of MRXS34 and points out the importance of intronic sequence analysis and the need for integrative functional studies in the interpretation of sequence variants.

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Human G protein-coupled receptor 56 (GPR56) is encoded by gene ADGRG1 from chromosome 16q21 and is homologously encoded in mice, at chromosome 8. Both 687 and 693 splice forms are present in humans and mice. GPR56 has a 381 amino acid-long N-terminal extracellular segment and a GPCR proteolysis site upstream from the first transmembrane domain. GPR56 is mainly expressed in the heart, brain, thyroid, platelets, and peripheral blood mononuclear cells.Accumulating evidence indicates that GPR56 promotes the formation of myelin sheaths and the development of oligodendrocytes in the cerebral cortex of the central nervous system. Moreover, GPR56 contributes to the development and differentiation of hematopoietic stem cells, induces adipogenesis, and regulates the function of immune cells. The lack of GPR56 leads to nervous system dysfunction, platelet disorders, and infertility. Abnormal expression of GPR56 is related to the malignant transformation and tumor metastasis of several cancers including melanoma, neuroglioma, and gastrointestinal cancer. Metabolic disorders and cardiovascular diseases are also associated with dysregulation of GPR56 expression, and GPR56 is involved in the pharmacological resistance to some antidepressant and cancer drug treatments. In this review, the molecular structure, expression profile, and signal transduction of GPR56 are introduced, and physiological and pathological functions of GRP56 are comprehensively summarized.Attributing to its significant biological functions and its long N-terminal extracellular region that interacts with multiple ligands, GPR56 is becoming an attractive therapeutic target in treating neurological and hematopoietic diseases.