A novel homozygous intronic variant affecting splicing in the RYR1 gene contributes to fetal hydrops.
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ABSTRACT:
SUBMITTER: Hou W
PROVIDER: S-EPMC11359738 | biostudies-literature | 2024 Nov
REPOSITORIES: biostudies-literature
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A novel homozygous intronic variant affecting splicing in the <i>RYR1</i> gene contributes to fetal hydrops.
Hou Wei W Huang Guifang G Wei Hongyu H Li Wenwei W Huang Houfeng H Qiu Yuling Y Zhu Hengying H Han Huifeng H Chen Ping P Zhang Xue X
Genes & diseases 20240714 6
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Project description:BackgroundHypertrophic cardiomyopathy (HCM) is a genetic disease of the heart and the most common cause of sudden cardiac death in the young. HCM is considered a disease of the sarcomere owing to the large number of mutations in genes encoding sarcomeric proteins. The riddle lies in discovering how these mutations lead to disease. As a result, treatments to prevent and/or treat HCM are limited to invasive surgical myectomies or ablations. The A31P variant of cardiac myosin binding protein-C, encoded by MYBPC3, was found to be more prevalent in a cohort of Maine Coon cats with HCM. However, other mutations in MYBPC3 and MYH7 have also been associated with HCM in cats of other breeds. In this study, we expand the spectrum of genes associated with HCM in cats.ResultsNext Generation Whole Genome sequencing was performed using DNA isolated from peripheral blood of a Maine Coon with cardiomyopathy that tested negative for the MYBPC3 A31P variant. Through risk stratification of variants, we identified a novel, homozygous intronic variant in cardiac troponin T (TNNT2). In silico analysis of the variant suggested that it may affect normal splicing of exon 3 of TNNT2. Both parents tested heterozygous for the mutation, but were unaffected by the disease. Echocardiography analyses revealed that the proband had shown early onset congestive heart failure, which is managed with a treatment regime including ACE and aldosterone inhibitors.ConclusionIn summary, we are the first to demonstrate the association between TNNT2 mutations and HCM in felines, suggesting that this gene should be included in the testing panel of genes when performing genetic testing for HCM in cats.
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2023-05-19 | GSE185943 | GEO
Project description:BackgroundSpondylocostal dysostosis 4 (SCDO4) is characterized by short stature (mainly short trunk), dyspnea, brain meningocele, and spina bifida occulta, which is caused by homozygous or compound heterozygous HES7 (HES family bHLH transcription factor 7) variants. The incidence of SCDO4 remains unknown due to the extremely low number of cases. This study reveals a novel homozygous HES7 splicing variant causing SCDO4 and reviews all the previously reported HES7 variants and corresponding symptoms, providing a comprehensive overview of the phenotypes and genotypes of HES7 variants.Case presentationThis case report focuses on a Chinese neonate who was first hospitalized for tachypnea, cleft palate, and short trunk. After a series of auxiliary examinations, the patient was also found to have deformities of vertebrae and rib, left hydronephrosis, and patent foramen ovale. He underwent surgery for congenital hydronephrosis at 5 months old and underwent cleft palate repair when he was 1 year old. After two and half years of follow-up, the boy developed normally. A novel homozygous HES7 splicing variant (c.226+1G>A, NM_001165967.2) was identified in the proband by whole-exome sequencing and verified by Sanger sequencing. The variant was inherited from both parents and minigene assays demonstrated that this variant resulted in the retention of intron3 in the HES7 transcript. Including this case, a total of six HES7 variants and 13 patients with SCDO4 have been reported.ConclusionsOur findings expand the genotype-phenotype knowledge of SCDO4 and provide new evidence for genetic counseling.
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Project description:BackgroundAbout 31 individuals with CLTC variants have been reported worldwide, and all reported individuals have motor and mental retardation. CLTC is known to lead to intellectual developmental disorder, autosomal dominant 56. Few studies are focusing on the prenatal stage of the disease.MethodAn ultrasound examination was performed to obtain the prenatal phenotype. Whole-exome sequencing was used to find the pathogenic variant. Multiple computational tools predicted the conservation and deleteriousness. Minigene assay and western blot were utilized to investigate the effect on splicing of mRNA and protein expression.ResultHere we found a novel de novo variant of CLTC in a fetus. The fetus manifested bilateral choroid plexus cysts of the brain, hyperechogenic kidneys, and ventricular septal defect. A heterozygous variant c.3249 + 1G > C was identified in the fetus. This position was conserved and the variant was predicted to be deleterious. Minigene assay revealed the presence of a truncating transcript with the retention of intron 20. Western blot result showed the c.3249 + 1G > C variant elicited degradation of the protein.ConclusionTo the best of our knowledge, our study identified a novel de novo variant of CLTC and provided the earliest clinical characteristic of the CLTC variant at the prenatal stage. The functional experiment suggested the variant caused the altering of the RNA splicing and the protein expression. We extended the mutational spectrum of CLTC and provided guidance on genetic counseling.
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