Search Results (70)

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed. Full article

Background/Objectives: In digenic populations, all females produce males and females in their offspring. Monogenic populations are composed of gynogenic (female-producing) and androgenic (male-producing) females. A theoretical population genetic model for evolution of digenic to monogenic populations is presented here. Methods: A controlling gene was associated with each of the four processes that characterise monogenic populations: (1) oogenesis is conventional, whereas spermatogenesis is unusual and it is characterised by the exclusive formation of X-bearing sperm (gene (s)), i.e., the paternal chromosomes are eliminated so that only the maternal ones are transmitted to the next generation; (2) the X chromosome that is eliminated in the zygote is the one inherited from the father (gene r); (3) an imprinting process occurs in the mother (gene g), which protects the maternally inherited X chromosome from elimination in the zygote and the whole maternal chromosome complement in spermatogenesis; (4) a maternal factor is produced during oogenesis (gene e), which inactivates the elimination factor [r] in the zygote, thus controlling the elimination of the paternal X chromosome. The sequences of emergence of the genes (e s r g) that transform a digenic population into a monogenic one were analysed. Results: The following evolutionary sequences were found: (1) the sequence (r s e) under dominant conditions of gene (s) and recessive conditions of gene (r); and (2) the sequences (s r e), (r s e), and (e s r) under recessive conditions of gene (s) and gene (r). It was also found that the process of genomic imprinting is a necessary condition for the generation of a monogenic population. Furthermore, a quantitative change in the interaction between the elimination factor and its maternal inhibitor modifies the genotypic formula of the monogenic state. Conclusions: The number and types of evolutionary transitions of a digenic to a monogenic population depends on the dominant or recessive characteristic of the newly emerging genes. The imprinting process must already be present in the digenic population from which the monogenic one evolves; otherwise, the population cannot reach the monogenic state. Full article

Lobed leaves play a critical role in enhancing the productivity of sprawling crops like zucchini by improving light capture and boosting photosynthesis. However, the genetic basis in zucchini remains largely unknown. Here, we developed an F₂ population from a cross between the entire-leaf cultivar ‘LR’ and the deeply lobed cultivar ‘Xi’. Genetic analysis showed that the non-lobed trait is dominant, with the F₂ segregation ratios (~9 entire:6 shallowly lobed:1 deeply lobed) indicating digenic inheritance. Using bulked segregant analysis sequencing (BSA-seq) and kompetitive allele-specific PCR (KASP) marker analysis, we identified a major effect locus at a 79.8 kb interval on chromosome 10. Within in this interval, gene expression profiling and annotation indicated CpARF6, encoding an auxin response factor, to be the prime candidate gene. Sequencing analysis revealed five nonsynonymous mutations in this gene, including a critical serine-to-leucine substitution at position 335 within the auxin response domain, which is likely a loss function mutation. Our findings establish CpARF6 as a critical regulator of lobed leaf formation in zucchini, providing valuable insights for both leaf development studies and zucchini breeding. Full article

Inherited retinal dystrophies (IRDs) are clinically and genetically heterogeneous disorders. Most IRDs follow a monogenic inheritance pattern. However, an increasing number of unresolved cases suggest the possible contribution of oligogenic or digenic mechanisms. Here, we report two ultra-rare missense variants—AIPL1 R302L and BBS2 P134R—that co-segregate with early-onset nonsyndromic retinal degeneration in affected individuals from a non-consanguineous family. We performed a multi-level computational investigation to assess whether these variants may act through a convergent pathogenic mechanism. Using AlphaFold2-predicted structures, we modeled both wild-type and mutant proteins, introduced point mutations, and performed energy minimization and validation. FoldX, DynaMut2, and DUET all predicted destabilizing effects at the variant sites, corroborated by local disruption of secondary structure and altered surface electrostatics. Comparative docking (via HDOCK and ClusPro) identified a putative interaction interface between the TPR domain of AIPL1 and the β-sheet face of BBS2. This interface was destabilized in the double-mutant model. At the systems level, transcriptomic profiling confirmed co-expression of AIPL1 and BBS2 in human retina and fetal eye, while functional enrichment analysis highlighted overlapping involvement in ciliary and proteostasis pathways. Network propagation suggested that the two proteins may converge on shared interactors relevant to photoreceptor maintenance. Collectively, these in silico results provide structural and systems-level support for a candidate digenic mechanism involving AIPL1 and BBS2. While experimental validation remains necessary, our study proposes a testable mechanistic hypothesis and underscores the value of computational approaches in uncovering complex genetic contributions to IRDs. Full article

Background/Objectives: Alport syndrome (AS) predominantly presents with X-linked inheritance worldwide. However, the epidemiological landscape remains poorly characterized, particularly among ethnic minority groups like the Roma minority in Slovakia. Our study aimed to investigate the inheritance patterns of AS in this region and determine whether a distinct pattern predominates. Methods: Selective genetic screening for pathogenic variants previously occurring in Slovakia was performed. Samples from patients with persistent (familial) hematuria ± hearing loss who had not yet undergone biopsy or genetic testing were analyzed by high-resolution melting analysis. The prevalence of AS per million (pm) population was calculated by adding information on patients with previously confirmed AS. Results: Twenty-five new cases of ARAS, one digenic form, and two cases of XLAS were identified by screening. In total, we collected information on 46 patients with genetically or bioptically confirmed AS in the region of eastern Slovakia, corresponding to a prevalence of 29 pm population. The c.1598G>A (p.Gly533Asp) pathogenic variant of the collagen type IV alpha 4 chain, which follows an autosomal recessive inheritance pattern, was the most prevalent variant that was exclusively confirmed in Roma patients (n = 35), suggesting a founder effect. Within the Roma community, the prevalence of ARAS (the most prevalent inheritance pattern) corresponds to 133 pm of the Roma population, based on midpoint population estimates. Conclusions: Our findings demonstrate a unique genetic profile of AS in the Roma population, characterized by a high prevalence of ARAS, with implications for genetic counseling and screening strategies. Full article

Variants in COL4A3 and COL4A4 cause autosomal dominant and recessive Alport syndrome, yet data on their distribution and clinical expression in different populations remain limited. This study investigated genotype–phenotype correlations and the distribution of COL4A3/COL4A4 variants in a Lithuanian Alport syndrome cohort. A total of 221 individuals from Lithuania were analyzed for COL4A3 and COL4A4 variants using either next-generation sequencing or Sanger sequencing in order to assess variant distribution and associated clinical features. Only individuals with pathogenic, likely pathogenic, or uncertain significance variants were included. Fifty-two individuals (38 index cases) with pathogenic, likely pathogenic, or variants of uncertain significance were identified, as follows: forty-eight were heterozygous, four had autosomal recessive, and four had digenic Alport syndrome. COL4A3 variants were found in 9.5% (21/221) and COL4A4 in 17.6% (39/221). Among the 28 identified variants, 18 were novel. Glycine substitutions (n = 8) were the most frequent and associated with worse kidney outcomes and increased hearing abnormalities. Hematuria was diagnosed significantly earlier than proteinuria (p = 0.05). Most individuals with autosomal dominant Alport syndrome had normal kidney function (eGFR > 90 mL/min/1.73 m²), while those with autosomal recessive Alport syndrome had more severe disease. Kidney failure occurred in 2/4 (50%) autosomal recessive Alport syndrome and 2/48 (4%) autosomal dominant Alport syndrome cases. A significant inverse correlation was found between eGFR and age in proteinuric individuals (r = –0.737; p = 0.013). This study expands knowledge of Alport syndrome in the Lithuanian population and contributes novel variant data to the global Alport syndrome genetic database. Full article

Grain protein content (GPC) is gaining attention due to increasing consumer demand for nutritious foods. The present study carried out at ICAR-IIRR, Hyderabad, focused on the identification of quantitative trait loci (QTLs) linked with GPC and other quality traits. We utilized a population of 188 F₂ individuals developed from BPT 5204 (low GPC) X JAK 686 (high GPC) for QTL analysis. QTL analysis yielded four significant QTLs for GPC, three for amylose content, and multiple QTLs for other quality traits. qPC1.2, a major QTL in milled rice, was located in the marker interval RM562-RM11307 on chromosome 1 with an LOD value of 4.4. qPC1.2 explained 15.71% of the phenotypic variance (PVE). Additionally, the Interval Mapping for Epistatic QTLs (IM-EPI) method detected 332 pairs of di-genic epistatic QTLs. Fifteen QTLs exhibited a positive additive effect, indicating that the contributing allele(s) was from JAK 686. Five F₂ plants, viz., F₂-140, F₂-12, F₂-7, F₂-147, and F₂-41, exhibited a high GPC of 14.67%, 14.36%, 14.32%, 13.60%, and 13.36%, respectively. Additionally, these plants also exhibited high per-plant grain yield (~17.0–29.0 g) with desirable agronomic traits. The QTLs identified are valuable resources for developing high-grain-protein varieties with high grain yield and desirable quality traits. Full article

Background: Meniere’s disease (MD) is a set of rare disorders that affects >4 million people worldwide. Individuals with MD suffer from episodes of vertigo associated with fluctuating sensorineural hearing loss and tinnitus. Hearing loss can involve one or both ears. Over 10% of the reported cases are observed in families, suggesting its significant genetic contribution. The condition is polygenic with >20 genes, and several patterns of inheritance have been reported, including autosomal dominant, autosomal recessive, and digenic inheritance across multiple MD families. Preclinical research using animal models has been an indispensable tool for studying the neurophysiology of the auditory and vestibular systems and to get a better understanding of the functional role of genes that are involved in the hearing and vestibular dysfunction. While mouse models are the most used preclinical model, this review analyzes alternative animal and non-animal models that can be used to study MD genes. Methods: A literature search of the 21 genes reported for familial MD and the preclinical models used to investigate their functional role was performed. Results: Comparing the homology of proteins encoded by these genes to other model organisms revealed Drosophila and zebrafish as cost-effective models to screen multiple genes and study the pathophysiology of MD. Conclusions: Murine models are preferred for a quantitative neurophysiological assessment of hearing and vestibular functions to develop drug or gene therapy. Full article

Background: Alport syndrome (AS) is one of the most common monogenic kidney disorders. Recent studies have highlighted the modifier effect of variants involving podocyte and non-collagenous extracellular matrix (ECM) proteins in AS. Methods: We report a case series of eight patients with genetically proven AS and simultaneous variants involving podocyte and non-collagenous ECM proteins. Our aim is to describe the influence of such variants on the phenotype of patients with AS. Results: We identified 10 different type IV collagen variants. Patients were diagnosed with autosomal dominant (3/8), autosomal recessive (2/8), digenic (2/8) and X-linked AS (1/8). There were eight different variants involving podocyte and non-collagenous ECM proteins. The genes involved were CRB2, LAMA5, LAMB2, NUP107, MYO1E and PLCE1. Four patients (LAMB2, LAMA5 and PLCE1 variants) presented with nephrotic syndrome or nephrotic range proteinuria. Two patients had hearing loss. Most patients (7/8) had a family history of kidney disease. Two patients (LAMB2 and LAMA5 variants) were diagnosed with focal segmental glomerulosclerosis. Two patients developed end-stage kidney disease (LAMA5, MYO1E and NUP107 variants). Conclusions: Although mutations of podocyte and ECM proteins do not have phenotypic expression in monoallelic form, the presence of such variants could explain the phenotypic variability of AS. Full article

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development. Full article

Understanding the correlation between genotype and phenotype remains challenging for modern genetics. Digenic network analysis may provide useful models for understanding complex phenotypes that traditional Mendelian monogenic models cannot explain. Clinical data, whole exome sequencing data, in silico, and machine learning analysis were combined to construct a digenic network that may help unveil the complex genotype–phenotype correlations in a child presenting with inherited seizures and thrombocytopenia. The proband inherited a maternal heterozygous missense variant in SCN1A (NM_001165963.4:c.2722G>A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A>C). In silico analysis showed that these two variants may be pathogenic for inherited seizures and thrombocytopenia in the proband. Moreover, focusing on 230 epilepsy-associated genes and 35 thrombopoiesis genes, variant call format data of the proband were analyzed using machine learning tools (VarCoPP 2.0) and Digenic Effect predictor. A digenic network was constructed, and SCN1A and MYH9 were found to be core genes in the network. Further analysis showed that MYH9 might be a modifier of SCN1A, and the variant in MYH9 might not only influence the severity of SCN1A-related seizure but also lead to thrombocytopenia in the bone marrow. In addition, another eight variants might also be co-factors that account for the proband’s complex phenotypes. Our data show that as a supplement to the traditional Mendelian monogenic model, digenic network analysis may provide reasonable models for the explanation of complex genotype–phenotype correlations. Full article

The tiller angle, which is an important agronomic trait, determines plant architecture and greatly influences the grain yield of rice. In this study, a population of chromosome segment substitution lines derived from a cross between a japonica variety with a compact plant architecture—Koshihikari—and an indica variety with a spread-out plant architecture—Nona Bokra—was used to investigate the genetic basis of the tiller angle. Five quantitative trait loci (qTA1, qTA5, qTA9-1, qTA9-2, and qTA11) for the tiller angle were detected on chromosomes 1, 5, 9, 9, and 11 in two different environments. The phenotypic variation in these QTLs ranged from 3.78% to 8.22%. Two pairs of digenic epistatic QTLs were detected in Lingshui. The epistatic interaction explained 15.19% and 13.60% of the phenotypic variance, respectively. Among the five QTLs, qTA9-2 was detected in both environments. An F₂ mapping population containing the qTA9-2 QTL was established. The location of qTA9-2 was narrowed down to a 187 kb region between InDel markers M9 and M10 on chromosome 9. Thirty open reading frames (ORFs), including TAC1, a gene known to regulate the tiller angle, were identified in this region. The gene sequencing results suggested that a base substitution from G to A at position 1557 in the 3′-untranslated region led to a difference in the expression of qTA9-2 in Koshihikari and Nona Bokra. These findings provide a potential gene resource for the improvement of rice plant architecture. Full article

Background/Objectives: BRCA1, BRCA2, ATM, and CHEK2 are known cancer predisposition genes (CPGs), but tumor risk in patients with simultaneous pathogenic variants (PVs) in CPGs remains largely unknown. In this study, we describe six patients from five families with multiple cancers who coinherited a combination of PVs in these genes. Methods: PVs were identified using NGS DNA sequencing and were confirmed by Sanger. Results: Families 1, 2, and 3 presented PVs in BRCA2 and ATM, family 4 in BRCA2 and BRCA1, and family 5 in BRCA2 and CHEK2. PVs were identified using NGS DNA sequencing and were confirmed by Sanger. The first family included patients with kidney, prostate, and breast cancer, in addition to pancreatic adenocarcinomas. In the second family, a female had breast cancer, while a male from the third family had prostate, gastric, and pancreatic cancer. The fourth family included a male with pancreatic cancer, and the fifth family a female with breast cancer. Conclusions: The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double-heterozygous patients associated with PVs in HR-related CPGs. Therefore, in families with patients who differ from other family members in terms of phenotype, age of diagnosis, or type of cancer, the cascade testing needs to include the study of other CPGs. Full article

Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders. Full article

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. Full article