Hypoplastic left heart syndrome (HLHS) is a rare but fatal birth defect in which the left side of the heart is underdeveloped. HLHS accounts for 2% to 4% of congenital heart anomalies. Whole genome sequencing (WGS) was conducted for a family trio consisting of a proband and his parents. A homozygous rare variant was detected in the PTPRB (Protein Tyrosine Phosphatase Receptor Type B) gene of the proband by functional annotation and co‐segregation analysis. Sanger sequencing was used to confirm genotypes of the variant. The in silico prediction tools, including Mutation Taster, SpliceAI, and CADD, were used to predict the impact of the mutation. The allele frequencies across populations were compared based on multiple databases, including “1000 genomes” and “gnomAD”. We used two vectors (pcMINI and pcDNA3.1) to generate a minigene construct to validate the mutational effect at the transcriptional level. Family‐based WGS analyses showed that only a homozygous splice acceptor variant (NC_000012.12: g.70636068T>G, NM_001109754.4: c.56‐2A>C, NG_029940.2: g.6373A>C) at the exon‐intron border of PTPRB gene associates with HLHS. This variant is also within the region with the enhancer activity based on UCSC genome annotation. Genotyping and Sanger sequencing revealed that the proband's parents are heterozygous for this variant. Evolutionary conservation analysis revealed that the site (NC_000012.12: g.70636068) is extremely conserved across species, supporting the evolutionary functional constraints of the ancestral wild type (T). In silico tools universally predicted a deleterious or disease‐causing impact of the mutation from T to G. The mutation was not found in the 1000 genomes and gnomAD databases, which indicates that this mutation is very rare in most human populations. A splicing assay indicated that the mutated minigene caused aberrant splicing of mRNA, in which a 3 bp missing in the second exon resulted in the deletion of one amino acid (NP_001103224.1:p.Glu19del) compared to the normal protein of PRPTB (also the VE‐PTP). Structure prediction revealed that the deletion occurred within the C‐region of the signal peptide of VE‐PTP, suggesting signal peptide‐related defects as a potential mechanism for the HLHS cellular pathogeny. We report a rare homozygous variant with splicing error in PTPRB associated with HLHS. Previous model species studies revealed conserved functions of PTPRB in cardiovascular and heart development in mice and zebrafish. Our study is the first report to show the association between PTPRB and HLHS in humans.

BackgroundMultiple evidence has suggested complex interaction between sex hormones and epilepsy. However, whether there exists a causal association and the effect direction remains controversial. Here we aimed to examine the causative role of hormones in the risk of epilepsy and vice versa.MethodsWe conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone (N = 425,097), estradiol (N = 311,675) and progesterone (N = 2,619), together with epilepsy (N = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males (N = 206,927).ResultsGenetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83–0.98, P = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88–0.97, P = 9.18E-04), but not in females. Such association was further verified in the replication stage (OR: 0.44, 95% CI: 0.23–0.87, P = 0.017). In contrast, no association was identified between testosterone, progesterone and the risk of epilepsy. In the opposite direction, epilepsy was not causally associated with sex hormones.ConclusionThese results demonstrated higher estradiol could reduce the risk of epilepsy, especially in males. Future development of preventive or therapeutic interventions in clinical trials could attach importance to this.

Hematologic abnormalities was observationally associated with the susceptibility of primary biliary cholangitis (PBC). However, the conclusion is still controversial and whether there exists a causal association remains elusive. Here we aimed to explore the causative role of hematological traits in the risk of PBC. We conducted two-sample and multivariable Mendelian randomization analyses based on summary statistics from previous large genome-wide association studies. Totally twelve red blood cell and six white blood cell traits were analyzed. Genetically determined higher hemoglobin level was significantly associated with a reduced risk of PBC (OR: 0.62, 95% CI: 0.47-0.81, P: 5.59E−04). Meanwhile, higher hematocrit level was nominally associated with reduced risk of PBC (OR: 0.73, 95% CI: 0.57-0.93, P: 0.01). These results could help better understand the role of hematological traits in the risk of PBC, and provide potential targets for the disease prevention and treatment.