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Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia-associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen-2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage-gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.

Background Hypophosphatemic rickets, including familial hypophosphatemic vitamin D-resistant rickets, which commonly manifests in childhood, is generally hereditary. X-linked dominant hypophosphatemic rickets (XLH, MIM307800), caused by inactivating mutations in the PHEX gene, is the most common form. This study aimed to identify the gene mutations responsible for three cases of XLH and its clinical phenotype. Methods We conducted a genetic diagnosis and clinical phenotypic linkage analysis of three pedigrees with XLH. Three probands finally diagnosed as XLH were analyzed by next-generation sequencing (NGS). Sanger sequencing was used for mutation scanning in other family members. Results For the three patients with XLH, the age of onset ranged from 1.5 to 2 years and their heights were less than three standard deviations (SDs) below the median. The patients exhibited curved deformities in both lower limbs, hypophosphatemia, elevated serum FGF23 levels and elevated levels of blood alkaline phosphatase, with normal levels of blood parathyroid hormone (PTH) and calcium. X-ray analysis of the limbs and chest revealed characteristic rickets signs. Three candidate pathogenic mutations were identified in PHEX (NM_000444.5): c.433G>T (p.Glu145*, p.E145*) in exon 4, c.1735G>A (p.Gly579Arg, p.G579R) (rs875989883) in exon 17 and c.2245T>C (p.Trp749Arg, p.W749R) in exon 22. The nonsense mutation (p.E145*) in PHEX is novel and is predicted to cause a truncation of the encoded protein, resulting in loss of function. Conclusions The novel nonsense mutation (p.E145*) in PHEX is possibly involved in inherited XLH.