UNASSIGNED: Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H Member 2 (KCNH2) gene are known to cause Long QT syndrome through an autosomal dominant inheritance pattern. However, as of now, there have been no reports of any KCNH2 variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender.
UNASSIGNED: Whole-exome sequencing (WES) was conducted on the proband to identify pathogenic variants. Subsequently, Sanger sequencing was employed to validate the identified likely pathogenic variants in all family members.
UNASSIGNED: We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel KCNH2 missense variant (p.Val630Gly, c.1889 T>G) as the causative factor for the family\'s phenotype. Within this family, all three male carriers of the KCNH2 variant carriers exhibited the Long QT syndrome phenotype: one experienced sudden death during sleep, another received an implantable cardioverter defibrillator (ICD), and a younger man displayed a prolonged QTc interval without any instances of syncope or malignant arrhythmia to date. Interestingly, the middle-aged female carrier showed no Long QT Syndrome phenotype. However, her offspring, diagnosed with Turner syndrome (45, X) and also a carrier of this variant, experienced frequent syncope starting at 12 years old and was diagnosed with Long QT syndrome, leading to an ICD implantation when she was 15 years old. These observations suggest that the manifestation of Long QT syndrome associated with this KCNH2 variant exhibits incomplete penetrance influenced by gender within this family, indicating potential protective mechanisms against the syndrome in females affected by this variant.
UNASSIGNED: Our investigation has led to the identification of a novel pathogenic KCNH2 variant responsible for Long QT syndrome within a familial context characterized by gender-selective, incomplete penetrance. This discovery highlights a unique pathogenic inheritance pattern for the KCNH2 gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the KCNH2 gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.

Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.

Noonan syndrome (NS)/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case.
In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of PTPN11 were searched from 2000 to 2022.
We present a case of a proband with a PTPN11 variant (c.1492C > T/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the PTPN11 p.Arg498Trp variant, cardiac abnormalities (6/11), facial dysmorphism (7/11), skin pigmentation (4/11), growth problems (4/11), and sensorineural hearing loss (2/11) have been observed. NS/NSML patients with the PTPN11 p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated PTPN11.
Paternally inherited NS/NSML caused by a PTPN11 p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene-gene interactions, gene-environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype.

BACKGROUND: Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations.
RESULTS: We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change.
CONCLUSIONS: With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.

Inherited cardiomyopathies represent a highly heterogeneous group of cardiac diseases. DNA variants in genes expressed in cardiomyocytes cause a diverse spectrum of cardiomyopathies, ultimately leading to heart failure, arrythmias, and sudden cardiac death. We applied massive parallel DNA sequencing using a 72-gene panel for studying inherited cardiomyopathies. We report on variants in 25 families, where pathogenicity was predicted by different computational approaches, databases, and an in-house filtering analysis. All variants were validated using Sanger sequencing. Familial segregation was tested when possible. We identified 41 different variants in 26 genes. Analytically, we identified fifteen variants previously reported in the Human Gene Mutation Database: twelve mentioned as disease-causing mutations (DM) and three as probable disease-causing mutations (DM?). Additionally, we identified 26 novel variants. We classified the forty-one variants as follows: twenty-eight (68.3%) as variants of uncertain significance, eight (19.5%) as likely pathogenic, and five (12.2%) as pathogenic. We genetically characterized families with a cardiac phenotype. The genetic heterogeneity and the multiplicity of candidate variants are making a definite molecular diagnosis challenging, especially when there is a suspicion of incomplete penetrance or digenic-oligogenic inheritance. This is the first systematic study of inherited cardiac conditions in Cyprus, enabling us to develop a genetic baseline and precision cardiology.

BACKGROUND: Mutations in PTH1R are associated with Jansen-type metaphyseal chondrodysplasia (JMC), Blomstrand osteochondrodysplasia (BOCD), Eiken syndrome, enchondroma, and primary failure of tooth eruption (PFE). Inheritance of the PTH1R gene can be either autosomal dominant or autosomal recessive, indicating the complexity of the gene. Our objective was to identify the phenotypic differences in members of a family with a novel PTH1R mutation.
METHODS: The proband was a 13-year, 6-month-old girl presenting with short stature, abnormal tooth eruption, skeletal dysplasia, and midface hypoplasia. The brother and father of the proband presented with short stature and abnormal tooth eruption. High-throughput sequencing was performed on the proband, and the variant was confirmed in the proband and other family members by Sanger sequencing. Amino acid sequence alignment was performed using ClustalX software. Three-dimensional structures were analyzed and displayed using the I-TASSER website and PyMOL software.
RESULTS: High-throughput genome sequencing and Sanger sequencing validation showed that the proband, her father, and her brother all carried the PTH1R (NM_000316) c.1393G>A (p.E465K) mutation. The c.1393G>A (p.E465K) mutation was novel, as it has not been reported in the literature database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the p.E465K variant was considered to have uncertain significance. Biological information analysis demonstrated that this identified variant was highly conserved and highly likely pathogenic.
CONCLUSIONS: We identified a novel heterozygous mutation in the PTH1R gene leading to clinical manifestations with incomplete penetrance that expands the spectrum of known PTH1R mutations.

No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria.

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical \'AnkB syndrome\' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function in vivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel in vivo animal model. At baseline, young AnkBp.E1458G+/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G+/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G+/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G+/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G+/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in in vivo cardiac function as well as the impact of single AnkB loss-of-function variants in vivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.

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