Background Cardiac conduction disease (CCD) is a common cardiovascular disease which can lead to life‐threatening conditions. The importance of heredity in CCD has been realized in recent years. Several causal genes have been found to be implicated in CCD such as SCN5A, TRPM4, SCN1B, TNNI3K, LMNA, and NKX2.5. To date, only four genetic mutations in TNNI3K have been identified related to CCD. Methods Whole‐exome sequencing (WES) was carried out in order to identify the underlying disease‐causing mutation in a Chinese family with CCD. The potential mutations were confirmed by Sanger sequencing. Real‐time qPCR was used to detect the level of TNNI3K mRNA expression. Results A nonsense mutation in TNNI3K (NM_015978.2: g.170891C > T, c.1441C > T) was identified in this family and validated by Sanger sequencing. Real‐time qPCR confirmed that the level of TNNI3K mRNA expression was decreased compared with the controls. Conclusions This study found the first nonsense TNNI3K mutation associated with CCD in a Chinese family. TNNI3K harboring the mutation (c.1441C > T) implicated a loss‐of‐function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype‐phenotype correlations between TNNI3K mutations and CCD and indicating the importance of TNNI3K screening in CCD patients.

BackgroundThe SCN11A gene encodes the α-subunit of the Nav1. 9 channel, which is a regulator of primary sensory neuron excitability. Nav1.9 channels play a key role in somatalgia. Humans with the gain-of-function mutation R222S in SCN11A exhibit familial episodic pain. As already known, R222S knock-in mice carrying a mutation orthologous to the human R222S variant demonstrate somatic hyperalgesia. This study investigated whether Scn11aR222S/R222S mice developed visceral hyperalgesia and intestinal dysmotility.MethodsWe generated Scn11aR222S/R222S mice using the CRISPR/Cas9 system. The somatic pain threshold in Scn11aR222S/R222S mice was assessed by Hargreaves' test and formalin test. The excitability of dorsal root ganglia (DRG) neurons was assessed by whole-cell patch-clamp recording. Visceralgia was tested using the abdominal withdrawal reflex (AWR), acetic acid-induced writhing, and formalin-induced visceral nociception tests. Intestinal motility was detected by a mechanical recording of the intestinal segment and a carbon powder propelling test. The excitability of the enteric nervous system (ENS) could influence gut neurotransmitters. Gut neurotransmitters participate in regulating intestinal motility and secretory function. Therefore, vasoactive intestinal peptide (VIP) and substance P (SP) were measured in intestinal tissues.ResultsThe R222S mutation induced hyperexcitability of dorsal root ganglion neurons in Scn11aR222S/R222S mice. Scn11aR222S/R222S mice exhibited somatic hyperalgesia. In addition, Scn11aR222S/R222S mice showed lower visceralgia thresholds and slowed intestinal movements when compared with wild-type controls. Moreover, Scn11aR222S/R222S mice had lower SP and VIP concentrations in intestinal tissues.ConclusionsThese results indicated that Scn11aR222S/R222S mice showed visceral hyperalgesia and intestinal dysmotility.

Background: Dubin–Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the ABCC2 gene; it is characterized by chronic hyperbilirubinemia. Here, we report two pedigrees affected with DJS which were caused by three novel pathogenic ABCC2 mutations.Case summary: The two patients exhibited intermittent low-grade, predominantly conjugated hyperbilirubinemia and showed no other abnormalities. They were diagnosed clinically with DJS. Three novel pathogenic ABCC2 mutations—c.2980delA, c.1834C>T, and c.4465_4473delinsGGCCCACAG—were identified by whole-exome sequencing. These mutations could be responsible for DJS in the two pedigrees. The genetic test confirmed the diagnosis of DJS.Conclusion: These results contributed to the genetic diagnosis of the two patients with DJS and expanded the variant database for the ABCC2 gene.