Phenotypic Correlations Research Articles

Phenotypic and genetic characteristics of retinal vascular parameters and their association with diseases.

Fundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Using a fully automated image processing pipeline, we extract 17 different morphological vascular phenotypes, including median vessels diameter, diameter variability, main temporal angles, vascular density, central retinal equivalents, the number of bifurcations, and tortuosity, from over 130,000 fundus images of close to 72,000 UK Biobank subjects. We perform genome-wide association studies of these phenotypes. From this, we estimate their heritabilities, ranging between 5 and 25%, and genetic cross-phenotype correlations, which mostly mirror the corresponding phenotypic correlations, but tend to be slightly larger. Projecting our genetic association signals onto genes and pathways reveals remarkably low overlap suggesting largely decoupled mechanisms modulating the different phenotypes. We find that diameter variability, especially for the veins, associates with diseases including heart attack, pulmonary embolism, and age of death. Mendelian Randomization analysis suggests a causal influence of blood pressure and body mass index on retinal vessel morphology, among other results. We validate key findings in two independent smaller cohorts. Our analyses provide evidence that large-scale analysis of image-derived vascular phenotypes has sufficient power for obtaining functional and causal insights into the processes modulating the retinal vasculature.

Clinical and mutational signatures of CRB1-associated retinopathies: a multicentre study

BackgroundTo delineate the clinical and mutational signatures of patients with CRB1-associated retinopathies.MethodsThis multicentre retrospective cohort study involved 40 patients with CRB1 mutations and 40 age-matched and gender-matched inherited retinal diseases...

Studies on Path Coefficient Analysis and Correlation to Evaluate the Relationships between Yield and Its Components in Fenugreek (Trigonella foenum-graecum L.)

The present investigation was carried out for correlation and path coefficient analysis in Fenugreek (Trigonella foenum-graecum L.) The correlation of different traits with seed yield was examined both at phenotypic and genotypic levels and the study showed that genotypic correlation coefficient values were higher than the phenotypic values. This indicated that how much of phenotypic correlation coefficient are influenced by environment. The seed yield per plant was positive and significant with biological yield per plant, test weight and number of branches per plant at genotypic and phenotypic levels. The maximum direct positive effect on seed yield per plant was observed in biological yield per plant, harvest index, days to 50 per cent flowering, number of seed per pod, number of branches per plant and number of pods per plant. In the present investigation, genotypes viz., AFG-4 and RMT-303 were superior for seed yield per plant along with other traits like biological yield, test weight and number of pods per plant. These diverse genotypes can be used in future breeding programme of fenugreek.

Bayesian Evaluation of Growth Rates and Kleiber's Ratios in Harnali Sheep: Dissecting Maternal and Additive Genetic Contributions.

Understanding the genetic basis of growth and metabolic traits in sheep is crucial for improving production efficiency and sustainability. The current study aimed to estimate the genetic influences, both direct and maternal, on growth rate and Kleiber's ratio traits in Harnali sheep using pedigree data under Bayesian inference. The data pertained to 2404 animals spanned over 24 years (1998-2021). Fixed factors such as birth period, lamb sex and dam's weight at lambing were considered. The traits studied included average daily gains (ADGs) categorised into ADG1 (birth to weaning age), ADG2 (weaning to 6 months of age) and ADG3 (6-12 months of age), as well as corresponding Kleiber's ratios (KR1, KR2 and KR3). Six single-trait animal models were employed to estimate covariance components and heritabilities, integrating direct additive and maternal effects alongside significant fixed factors using THRGIBBS1F90 and POSTGIBBSF90 programmes. Direct heritability estimates were obtained for ADG1 (0.11 ± 0.05), ADG2 (0.06 ± 0.03), ADG3 (0.03 ± 0.03), KR1 (0.07 ± 0.03), KR2 (0.06 ± 0.03) and KR3 (0.05 ± 0.03). Maternal genetic effects have contributed significant particularly to pre-weaning traits. The study identified an antagonistic relationship between direct additive and maternal genetic effects. Positive genetic and phenotypic correlations emphasised the intricate relationship between growth and metabolic efficiency in Harnali sheep. The current study offers critical insights into the genetic basis of growth and metabolic traits in Harnali sheep, ultimately contributing to more efficient and sustainable sheep production systems.

Investigating genotype by environment interaction for beef cattle fertility traits in commercial herds in northern Australia with multi-trait analysis

BackgroundGenotype by environment interactions (GxE) affect a range of production traits in beef cattle. Quantifying the effect of GxE in commercial and multi-breed herds is challenging due to unknown genetic linkage between animals across environment levels. The primary aim of this study was to use multi-trait models to investigate GxE for three heifer fertility traits, corpus luteum (CL) presence, first pregnancy and second pregnancy, in a large tropical beef multibreed dataset (n = 21,037). Environmental levels were defined by two different descriptors, burden of heat load (temperature humidity index, THI) and nutritional availability (based on mean average daily gain for the herd, ADWG). To separate the effects of genetic linkage and real GxE across the environments, 1000 replicates of a simulated phenotype were generated by simulating QTL effects with no GxE onto real marker genotypes from the population, to determine the genetic correlations that could be expected across environments due to the existing genetic linkage only. Correlations from the real phenotypes were then compared to the empirical distribution under the null hypothesis from the simulated data. By adopting this approach, this study attempted to establish if low genetic correlations between environmental levels were due to GxE or insufficient genetic linkage between animals in each environmental level.ResultsThe correlations (being less than <0.8) for the real phenotypes were indicative of GxE for CL presence between ADWG environmental levels and in pregnancy traits. However, none of the correlations for CL presence or first pregnancy between ADWG levels were below the 5th percentile value for the empirical distribution under the null hypothesis from the simulated data. Only one statistically significant (P < 0.05) indication of GxE for first pregnancy was found between THI environmental levels, where rg = 0.28 and 5th percentile value = 0.29, and this result was marginal.ConclusionsOnly one case of statistically significant GxE for fertility traits was detected for first pregnancy between THI environmental levels 2 and 3. Other initial indications of GxE that were observed from the real phenotypes did not prove significant when compared to an empirical null distribution from simulated phenotypes. The lack of compelling evidence of GxE indicates that direct selection for fertility traits can be made accurately, using a single evaluation, regardless of environment.

Endocrine Perspective of Cutaneous Lichen Amyloidosis: RET-C634 Pathogenic Variant in Multiple Endocrine Neoplasia Type 2

Background: Medullary thyroid carcinoma (MTC), the third most frequent histological type of thyroid malignancy, may be found isolated or as part of multiple endocrine neoplasia type 2 (MEN2). One particular subtype of this autosomal dominant-transmitted syndrome includes an association with cutaneous lichen amyloidosis, although, generally, a tide genotype–phenotype correlation is described in patients who carry RET proto-oncogene pathogenic variants. Methods: Our objective was to provide an endocrine perspective of a case series diagnosed with RET-positive familial MTC associated with cutaneous primary lichen amyloidosis amid the confirmation of MEN2. Six members of the same family had cutaneous lesion with different features (from hyperpigmented, velvety to red/pink appearance) and four of them harbored a RET pathogenic variant at 634 codon (exon 11): c.1900T&gt;G, p.634G (TGC634CGC). Results: All six patients were females with the lesion at the interscapular region. Except for two women, four of these subjects were investigated and had MTC (three of them with postoperatory confirmation). The youngest affected individual was 6 years old. The three adult females were confirmed with RET pathogenic variant during their 30s, while the girl underwent the familial screening as a newborn. None of them had primary hyperparathyroidism until the present time, except for one subject, and two out of the three adults also had bilateral pheochromocytoma. Notably, all patients were rather asymptomatic from the endocrine perspective at the moment when endocrine tumor/cancer was confirmed, and the skin was progressively affected a few years before the actual MEN2 confirmation. Conclusions: This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly.

Common Genetic Influence on the Relationship Between Gaming Addiction and Attention Deficit Hyperactivity Disorder in Young Adults: A Twin Study.

Although the relationship between gaming addiction (GA) and attention deficit hyperactivity disorder (ADHD) is well established, the causal mechanism of this relationship remains ambiguous. We aimed to investigate whether common genetic and/or environmental factors explain the GA-ADHD relationship. We recruited 1413 South Korean adult twins (837 monozygotic [MZ], 326 same-sex dizygotic [DZ], and 250 opposite-sex DZ twins; mean age = 23.1 ± 2.8 years) who completed an online survey on GA and related traits. Correlational analysis and bivariate model-fitting analysis were conducted. Phenotypic correlation between GA and ADHD in the present sample was 0.55 (95% CI [0.51, 0.59]). Bivariate model-fitting analysis revealed that genetic variances were 69% (95% CI [64%, 73%]) and 68% (95% CI [63%, 72%]) for ADHD and GA respectively. The remaining variances (ADHD: 31%; GA: 32%) were associated with nonshared environmental variances, including measurement error. Genetic and nonshared environmental correlations between ADHD and GA were 0.68 (95% CI [0.62, 0.74]) and 0.22 (95% CI [0.13, 0.30]) respectively, which indicates that shared genes can explain 82% of the phenotypic correlation between ADHD and GA. Our study demonstrated that the ADHD-GA association was largely due to shared genetic vulnerability.

Genotype‒phenotype correlation in recessive DNAJB4 myopathy.

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547C > T, p.R183*; c.775C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.

Association of keel bone morphometry with keel bone damage and skeletal quality in the laying hen

ABSTRACT 1. The aim of this work was to identify a heritable keel bone phenotype with a correlation to keel bone damage and/or skeletal bone strength that could be easily measured in the living hen to aid selection to prevent welfare issues. 2. The scoring system used reflected the observed damage, keel bone dimensions and shape compared to traditional measurements of bone quality. 3. Increased keel bone damage was associated with poor humerus and tibia breaking strengths (p < 0.01). Bone damage was associated with higher whole keel density (p < 0.01) due to the effect of callus formation. 4. Keel bone depth and area was moderately heritable at indices of 0.32 and 0.40, respectively. Keel bone depth was genetically correlated with tibia (0.36) and humerus density (0.68) and keel bone area was correlated with humerus density (0.59). Deeper keel bones and those with larger areas had small, negative phenotypic correlations with keel bone damage (−0.07 and −0.11, respectively). The second principal component of keel bone shape represented the caudal section of the keel bone and cranial edge concavity. The third principal component represented the differences in the caudal tip of the keel bone, the concavity of the dorsal edge and convexity of the ventral edge. Heritability estimates were 0.44 and 0.39, respectively. 5. The results suggested that genetics contribute to morphometric traits. Hens with poorer skeletal quality are likely to accumulate more damage. Some of the traits may be a predictor of damage, although mid keel depth or concavity may simply reflect the effect of damage or deviation.

Inclusion of imputed genotypes from non-genotyped dairy cattle in a Thai multibreed genomic-polygenic evaluation.

This study assessed the impact of incorporating imputed SNP information from non-genotyped animals on genomic-polygenic evaluations in a Thai multibreed dairy population under various levels of imputation accuracy. Data encompassed pedigree and phenotypic records for 305-day milk yield (MY), 305-day fat (Fat), and age at first calving (AFC) from 12,859 first-lactation cows, and genotypic records of various densities from 4,364 animals. A set of 64 animals genotyped with GeneSeek Genomic Profiler 80K and with four or more genotyped progenies was defined as target animals to simulate imputation scenarios for non-genotyped individuals. Actual and imputed genotypes were utilized to construct three SNP sets. All SNP Sets contained actual and imputed SNP markers from genotyped animals. SNP Set 1 contained no SNPs from target animals, whereas SNP Set 2 incorporated imputed SNPs from target animals, and SNP Set 3 added actual SNPs from target animals. Genomic-polygenic evaluations were conducted using a 3-trait single-step model that included contemporary group, calving age, and heterozygosity as fixed effects and animal additive genetic and residual as random effects. The imputation accuracy was similar across non-genotyped animals irrespective of the number of genotyped progenies (average: 40.55%; range: 34.68% to 53.82%). Estimates of additive genetic and environmental variances and covariances for MY and AFC varied across SNP sets. SNP Sets 1 and 2 had slightly higher additive genetic and lower environmental variances and covariances than SNP Set 3. Heritabilities and additive genetic, environmental, and phenotypic correlations between MY, Fat, and AFC were similar across all SNP Sets. Spearman rank correlations between genomic-polygenic EBVs from SNP Sets 2 and 3 were high for all traits (0.9990±0.0003). Utilization of phenotypic and pedigree data from imputed non-genotyped animals enhanced the efficiency and cost-effectiveness of the genetic improvement program in the Thai multibreed dairy cattle population.

Genetic analysis of Vicia faba L.: Advancements, hereditary traits, and correlations in ‘Sakha 3’ × ‘Nubaria 3’

Genetic diversity, heritability, and genetic advance are crucial considerations in the field of plant breeding. This research aimed to evaluate these factors for traits related to yield in faba bean (Vicia faba L.), specifically focusing on the F3 and F4 generations resulting from the cross between ‘Sakha 3’ and ‘Nubaria 3’. In the initial season (2021/ 2022), 200 families from each F3 population were cultivated with specific spacing, and selection criteria included seed yield per plant (SYP) and the number of pods per plant (NPP). Top-performing plants were identified for the second cycle of pedigree selection. In the following season (2022/2023), the F4 families were arranged in a randomised complete block design. Traits like the number of branches per plant (NBP), NPP, SYP, and seed index (SI) showed substantial phenotypic and genotypic coefficients of variation, indicating their noteworthy variation. Phenotypic and genotypic correlation analyses showed positive associations between SYP and the NBP and NPP. Additionally, path coefficient analysis indicated that these traits had high positive direct effects on SYP. This research provides valuable insights into the genetic variability, heritability, and selection parameters for yield-related traits in faba bean, offering a foundation for future breeding programs aimed at improving yield and productivity.

A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever

Immunodeficiency 11B with atopic dermatitis (IMD11B, OMIM:617638) is rare primary immunodeficiency disease caused by germline dominant negative (DN) mutations in the CARD11 gene. Affected patients present with immune dysfunction, recurrent infections and atopic dermatitis. In this study, we sought to identify and characterize the genetic variant in one patient with periodic fever, recurrent infections, and eczema. Trio whole-exome sequencing (WES) was employed in this patient and her parents, and Sanger sequencing validated the potential pathogenic variant. In vitro functional study was performed to evaluate the pathogenicity of genetic variant identified. A very rare missense mutation (c.2324C > T, p.S775L) in CARD11 gene (NM_032415) was identified by WES in the patient but not her parents. Luciferase reporter assays and co-immunoprecipitation demonstrated mutation exerts a dominant-interfering effect on wild-type CARD11, inhibiting the activity of NF-κB. RNA sequencing analysis also confirmed that mutant CARD11 inhibited down-stream transcriptional activity of NF-κB. A review of literature doesn’t found significant genotype–phenotype correlation. We identified a vary rare DN CARD11 mutation, expanding the genetic and phenotypic spectrum of CARD11.

Genetic Perspectives on Feed Event, Meal and Feed Efficiency Traits in Bos taurus indicus Beef Cattle.

Electronic feeders record feeding behaviour as feed events by tracking the animal's in-out visits to the feeder. Another way to measure feeding behaviour is based on meals. However, the two approaches provide different outcomes. The objectives of this study were to estimate genetic parameters (heritabilities and genetic and phenotypic correlations) for feed event and meal traits, and their genetic and phenotypic correlations with feed efficiency traits in Nellore cattle. The present study analysed six feed event traits (DMIFE: dry matter intake per feed event, FED: feed event duration, TBFE: time between feed events, FTd: feeding time per day, FEd: feed events per day, and FR: feeding rate), six meal traits (DMIME: DMI per meal, MED: meal duration, TBME: time between meals, MC: meal criterion, MTd: meal time per day, and MEd: meals per day), and three feed efficiency traits (ADG: average daily gain, DMI, and RFI: residual feed intake). The traits were measured in feed efficiency tests of Nellore cattle (age = 280 ± 41 days and body weight = 258 ± 47 kg at enrolment). The MC was calculated for each animal and ranged from 1.70 to 64.0 min, i.e., any pair of feed events separated by less than the MC value was considered part of the same meal. The heritabilities and correlations were estimated by fitting univariate and bivariate animal models, respectively, using single-step genomic BLUP. The highest heritabilities for feed event traits were 0.35 ± 0.06 (FED), 0.39 ± 0.06 (FTd), and 0.50 ± 0.05 (FTd), and for meal traits were 0.31 ± 0.06 (MED) and 0.45 ± 0.06 (MTd). The genetic correlation between feed event traits and meal traits were weak. FR, FED, and FTd had moderate genetic correlations with RFI (-0.56 ± 0.11, 0.44 ± 0.11, 0.60 ± 0.08, respectively). These results indicate that more efficient animals spent less time at the feeder per feed event and per day, and eat faster compared to less efficient animals. In conclusion, feed event and meal traits must be treated as distinct groups of traits since the genetic and phenotypic correlations were, in general, weak to moderate. Among feed event versus meal traits, feed event traits are more favourable to explain the genetic relationships of feeding behaviour with feed efficiency-related traits.

Genome-wide association studies in a diverse strawberry collection unveil loci controlling agronomic and fruit quality traits.

Strawberries (Fragaria sp.) are cherished for their organoleptic properties and nutritional value. However, breeding new cultivars involves the simultaneous selection of many agronomic and fruit quality traits, including fruit firmness and extended postharvest life. The strawberry germplasm collection here studied exhibited extensive phenotypic variation in 26 agronomic and fruit quality traits across three consecutive seasons. Phenotypic correlations and principal component analysis revealed relationships among traits and accessions, emphasizing the impact of plant breeding on fruit weight and firmness to the detriment of sugar or vitamin C content. Genetic diversity analysis on 124 accessions using 44,408 markers denoted a population structure divided into six subpopulations still retaining considerable diversity. Genome-wide association studies for the 26 traits unveiled 121 significant marker-trait associations distributed across 95 quantitative trait loci (QTLs). Multiple associations were detected for fruit firmness, a key breeding target, including a prominent locus on chromosome 6A. The candidate gene FaPG1, controlling fruit softening and postharvest shelf life, was identified within this QTL region. Differential expression of FaPG1 confirmed its role as the primary contributor to natural variation in fruit firmness. A kompetitive allele-specific PCR assay based on the single nucleotide polymorphism (SNP) AX-184242253, associated with the 6A QTL, predicts a substantial increase in fruit firmness, validating its utility for marker-assisted selection. In essence, this comprehensive study provides insights into the phenotypic and genetic landscape of the strawberry collection and lays a robust foundation for propelling the development of superior strawberry cultivars through precision breeding.

Genetic assessment of productive and reproductive traits in Friesian, native, and crossbred cattle in Egypt

This study utilized a dataset comprising 3023 lactation records for Friesian cows, 596 records for Native cows (Baladi), and 1189 records for Crossbred cows spanning from 1994 to 2015. The objective was to estimate and assess genetic and phenotypic parameters and breeding values for 305-day milk yield (305-DMY), lactation period (LP), calving interval (CI), and days open (DO) within the Egyptian dairy context. The motivation for this research stemmed from the need to understand the genetic potential of different cattle genotypes in Egypt and identify opportunities for enhancing dairy production. Data were analyzed using the linear mixed model least squares and maximum likelihood (LSMLMW) and multiple-trait derivative-free restricted maximum likelihood (MTDFREML) programs. The analytical model included fixed effects such as season and year of calving, parity, and genotype groups, while random effects included animal and error. Unadjusted means for 305-DMY, LP, CI, and DO were calculated for each genotype group. Genotype groups significantly impacted all studied traits. Heritability estimates varied across genotype groups, with higher estimates observed in Crossbred (0.32, 0.26, 0.25, 0.23) and Native cows (0.26, 0.28, 0.28) compared to Friesian cows (0.24, 0.22, 0.16, 0.17) for productive and reproductive traits, respectively. Genetic correlations among traits ranged from 0.10 to 0.86 for the three genotype groups, while corresponding phenotypic correlations were generally small to moderate and positive. Regarding breeding values, the accuracy estimates suggested that both sires and cows could contribute to genetic improvement. This indicates the potential for enhancing dairy production through selective breeding strategies.

Among-family variations of wood-color parameters, decay resistance, total phenol, and total flavanol content in the heartwood of the third-generation Acacia mangium in Indonesia

Abstract To evaluate the inheritance of natural durability of Acacia mangium Willd., wood-color parameters (Y [lightness], x [red to green], and y [yellow to blue]), mass loss by a white-rot fungus (Trametes versicolor) and brown-rot fungus (Fomitopsis palustris), and three different extracts (methanol extract, total phenol, and total flavanol content) were measured using the inner and outer heartwood of 10-year-old trees from 20 half-sib families in the third-generation A. mangium in Indonesia. The broad-sense heritability (H 2) values were moderate to high for the wood-color parameters and mass loss by white- and brown-rot fungi (H 2 = 0.210–0.851) and low to moderate for three different extracts (H 2 = 0.000–0.576). Significant negative phenotypic correlations were found between the three different extracts and mass loss by T. versicolor and F. palustris. In addition, negative correlations were found between the wood-color parameters and three different extracts. Similar results were found between the total phenol content and y and between the total flavanol content and Y in genetic correlations. Therefore, A. mangium families with lower Y and y in heartwood could produce progenies with higher total phenol and total flavanol content, leading to higher natural decay resistance.

Functional characterisation of human recessive DIS3 variants in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is characterised by the loss or complete absence of ovarian activity in women under the age of 40. Clinical presentation of POI varies with phenotypic severity ranging from premature loss of menses to complete gonadal dysgenesis. POI is genetically heterogeneous with >100 causative gene variants identified thus far. The aetiology of POI varies from syndromic, idiopathic, monogenic to autoimmune causes the condition. Genetic diagnoses are beneficial to those impacted by POI as it allows for improved clinical management and fertility preservation. Identifying novel variants in candidate POI genes, however, is insufficient to make clinical diagnoses. The impact of missense variants can be predicted using bioinformatic algorithms but computational approaches have limitations and can generate false positive and false negative predictions. Functional characterisation of missense variants, is therefore imperative, particularly for genes lacking a well-established genotype:phenotype correlation. Here we used whole-exome sequencing (WES) to identify the first case of a homozygous missense variant in DIS3 (c.2320C > T; p.His774Tyr) a critical component of the RNA exosome in a POI patient. This adds to the previously described compound heterozygous patient. We perform the first functional characterisation of a human POI-associated DIS3 variant. A slight defect in mitotic growth was caused by the variant in a Saccharomyces cerevisiae model. Transgenic rescue of Dis3 knockdown in Drosophila melanogaster with human DIS3 carrying the patient variant led to aberrant ovarian development and egg chamber degeneration. This supports a potential deleterious impact of the human c.2320C > T; p.His774Tyr variant.

Clinical and molecular cytogenetic findings of cat eye syndrome and a 2-year-old patient with congenital aural atresia and hearing loss

BackgroundCat eye syndrome (CES) is a rare congenital disease frequently caused by a partial tetrasomy of the proximal long (q) arm of chromosome 22, due to a small supernumerary marker chromosome (sSMC). CES patients show remarkable phenotypic variability. Despite the progress of molecular cytogenetic technology, the cause of phenotypic variability and the genotype–phenotype correlations remain unknown.MethodsWe analyzed clinical and genetic data of a new patient with CES together with 27 previously reported ones with a confirmed genomic gain in the PubMed database between 2012 and 2023.ResultsWe reported a boy with CES carrying a 22q11.1-q11.21 duplication of 1.76 Mb tetrasomy (16888900_18644241, hg19) who presented currently rare or unreported clinical findings such as congenital aural atresia, hearing loss, PLSVC, and IVC. The results of the whole exome sequencing (WES) showed a heterozygous mutation of the GJB2 gene (NM_004004.6: exon2: c.109G > A). In addition, the results of our literature review showed that the presence of a classical sSMC was the most frequent cytogenetic abnormality in CES (82%). 63% of cases were in a homogenous state and 37% of cases were in a mosaic state. 72% of cases had a 1–2 Mb duplication. In the majority of CES patients the breakpoints in chromosome 22 are localized to a 50 kb region (18610000_18660000 bp). The CES critical region (CESCR) may be further delimited to a 0.3 Mb region (17799398_18111588 bp). Within this region CECR2, SLC25A18, ATP6V1E1, and BCL2L13 are strong candidate genes for causing the main CES phenotype. The ear anomalies are the most frequent features in CES patients (89%) and hearing loss was present in 36% of CES patients.ConclusionsThe phenotypic features in CES are highly variable. Our findings expand the symptom spectrum of CES and lay the foundation for better delineating the clinical phenotype, molecular cytogenetic features associated with CES and genotype–phenotype correlations. We recommend performing WES to rule out the involvement of other genetic factors in the patient’s phenotype. In addition, our findings also highlight the need for genetic counseling and recurrence risk assessment.

Genotype‒phenotype correlation in recessive DNAJB4 myopathy.

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547C > T, p.R183*; c.775C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181A > G, p.R61G). All patients were homozygous. All affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J-domain may predict a more severe phenotype.

Deciphering the Complexity of FSHD: A Multimodal Approach as a Model for Rare Disorders

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients’ care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype–phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.