A recurrent splice variant sheds light on 11beta-hydroxylase deficiency in a unique large cohort.

Context: Congenital adrenal hyperplasia (CAH) can be due to 11β-hydroxylase deficiency (11βOHD). Sporadic reports of 11βOHD are frequent but overviews on molecular landscape in some populations are lacking.

Objective: The aim of this research was to compile a genetic landscape from a 11βOHD cohort, and to report a novel yet recurrent splice variant.

Early onset multivalvular disease caused by a missense variant in lamin A/C.

Lamins A/C, coded by LMNA gene, are crucial for nuclear architecture preservation. Pathogenic LMNA variants cause a wide range of inherited diseases called "laminopathies". A subgroup is referred to "progeroid syndromes" characterized by premature aging and other manifestations including cardiac valve abnormalities.

Functional Evaluation of Splice Variants Using a Minigene Strategy.

Suspected splicing variants can be very challenging to evaluate more particularly when RNA samples are not available to perform RNA sequencing or when the gene of interest is expressed in specific tissues not easily reachable. One alternative strategy to study the potential splicing effect of a variant is to use the patient's DNA. Indeed, it is easily possible to amplify the region of interest and include it in the reporting system such as hybrid minigene, which could then be transfected in eukaryotic cells in order to estimate the impact of the mutated region in comparison to a wild-type version of the region.

Minigene splicing reporter assay: a high-stake tool for genetic diagnosis in familial hypobetalipoproteinemia.

Background & Aims: Familial hypobetalipoproteinemia 1 (FHBL-SD2) is the most common monogenic form of primary hypocholesterolaemia, related to truncating variants in the APOB gene encoding apolipoprotein B. Due to its high level of complexity, variants of uncertain significance (VUS) require further investigations. This study aims to demonstrate the value of setting minigene assays in the FHBL-SD2's genetic diagnosis.

SH3KBP1 promotes skeletal myofiber formation and functionality through ER/SR architecture integrity.

Dynamic changes in the arrangement of myonuclei and the organization of the sarcoplasmic reticulum are important determinants of myofiber formation and muscle function. To find factors associated with muscle integrity, we perform an siRNA screen and identify SH3KBP1 as a new factor controlling myoblast fusion, myonuclear positioning, and myotube elongation. We find that the N-terminus of SH3KBP1 binds to dynamin-2 while the C-terminus associates with the endoplasmic reticulum through calnexin, which in turn control myonuclei dynamics and ER integrity, respectively.

Cardiogenetics and uncertainty: Evaluation of professional vulnerability in France.

Scientific advances in genomics are transforming healthcare and prevention. However, they also increase situations of uncertainty, which in turn increase vulnerability not only for patients and their families but also for professionals. Cardiogenetics plays a crucial role in preventing sudden death in young individuals, but it can pose complex challenges for healthcare teams.

Mobile Element Insertion in the APOB Exon 3 Coding Sequence: A New Challenge in Hypobetalipoproteinemia Diagnosis.

Mobile elements (ME) can transpose by copy-and-paste mechanisms. A heterozygous insertion in APOB exon 3 coding sequence was suspected in a patient with hypobetalipoproteinemia (HBL), by gel electrophoresis of the PCR products. An insertion of a 85 bp fragment flanked by a polyA stretch and a target replication site duplication was identified as a ME insertion (MEI) from the AluYa5 subfamily, NM_000384.

Circulating Autoantibodies Targeting TREK-1 in Patients With Short-Coupled Ventricular Fibrillation.

Background: Short-coupled ventricular fibrillation (SCVF) is increasingly being recognized as a distinct primary electrical disorder and cause of otherwise unexplained cardiac arrest. However, the pathophysiology of SCVF remains largely elusive. Despite extensive genetic screening, there is no convincing evidence of a robust monogenic disease gene, thus raising the speculations for alternative pathogeneses.

Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants.

Background And Objective: Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders associated with significant morbidity and mortality for which substantial evidence for a genetic contribution was previously reported. We present a detailed molecular investigation of a cohort of 231 patients presenting with primary cardiomyopathy below the age of 18 years.

Methods: Cases with pediatric cardiomyopathies were analyzed using a next-generation sequencing (NGS) workflow based on a virtual panel including 57 cardiomyopathy-related genes.

CRISPR-Cas9 Engineering in Hypobetalipoproteinemia: A Promising Tool for Functional Studies of Novel Variants.

Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry missense variants of uncertain significance (VUS).

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.

Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.