Novel missense variant in TTN cosegregating with familial atrioventricular block

Huang

et al. 2020

Preprint

Self Cite

Background: Genetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes. Objective: To identify the association of non-obstructive azoospermia and the putative causative genetic factors. Design, setting, and participants: A single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients families. Outcome measurements and statistical analysis: Whole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes. Results and limitations: Totally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study. Conclusions: Five novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study. Patient summary: 133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center. All patients underwent semen analyses at least on three different occasions.

Section: Methodsmentioning

confidence: 99%

Whole exome sequencing identifies genes associated with non-obstructive azoospermia

Huang

et al. 2020

Preprint

Self Cite

“…Increasing evidence suggests that gene mutations and dysfunction of the conduction system during heart development may result in familial AVB [9][10][11][12] . However, only a few data are available regarding the pathophysiology of acquired AVB.…”

Section: Discussionmentioning

confidence: 99%

“…Progressive idiopathic fibrosis related to an aging process of the cardiac skeleton is the most common cause of chronic acquired AVB 2,[4][5][6][7][8] . It is generally accepted that familial and inherited AVB are caused by gene mutations and dysfunction of the conduction system during heart development [9][10][11][12] . In contrast, the pathophysiological mechanism of acquired AVB is currently unclear.…”

mentioning

confidence: 99%

Matrix metalloproteinase 1 1 G/2 G gene polymorphism is associated with acquired atrioventricular block via linking a higher serum protein level

Chen

Chang

Liou

2020

Sci Rep

in humans and animals demonstrated that modulation of MMP and RAS gene expression could lead to atrial fibrillation 19,20 , non-familial sick sinus syndrome 21 , and affect cardiac conduction after myocardial infarction 17 , apoptosis of the conductive system 22 and occurrence of ventricular arrhythmia 23. Here, we examined whether the polymorphisms of the genes encoding the MMPs and ACE could alter the disease susceptibility for acquired AVB by investigating the relationship between MMPs and ACE gene polymorphisms and disease susceptibility of acquired AVB. The results obtained indicated that MMP1 1 G/2 G gene polymorphism is associated with AVB via linking a higher serum protein level.

“…The average sequencing depth of the target region is ≥ 180X, and the proportion of sites with the average depth of the target region > 20 × is > 95%. Sanger sequencing of the identified potential pathogenic variant by whole exome sequencing was performed for the proband and his family members[ 7 ].…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel splicing mutation and genotype–phenotype correlations in rare PLS3-related childhood-onset osteoporosis

Feng

Zhu

et al. 2022

Orphanet J Rare Dis

Background X-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype–phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown. Methods Whole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD. Results We identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype–phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = − 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from − 2.9 to − 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05). Conclusions Our findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype–phenotype correlations.