Assessment of the quality of life in patients with LGMD. The case of transportinopathy.

The Quality of Life (QOL) is influenced by several disease-related factors, support, resources, expectations, and aspirations, within the disease-related concepts. The Individualized Neuromuscular Quality of Life (INQoL) is a validated muscle disease-specific measure of the QoL developed from the experiences of patients with muscle disease and can be used for people or large cohorts. This review of QoL in transportinopathy cases reports adjustments in an autosomal dominant (AD) LGMD, and a comparison is made with autosomal recessive (AR) LGMD evaluated by INQoL. The locus for this form of LGMD with AD inheritance was found on chromosome 7, and then identification of the gene and its encoded protein (transportin-3) was obtained in 2013. A large three-generation family with several branches in Spain and Italy was previously reported and described in detail. Some patients had an early onset weakness, but others had an adult onset of the disease, as late as 58 years. The severity of the appearance of the phenotype is correlated with QoL and progresses with age. Assessing the impact on their QoL is particularly relevant to know whether the treatment is reducing their suffering.

Genetic potential and inheritance pattern of agronomic traits in faba bean under free and infested Orobanche soil conditions.

BACKGROUND: Orobanche is an obligate parasite on faba bean in the Mediterranean region, causes considerable yield losses. Breeding tolerant faba bean genotypes to Orobanche is pivotal to sustain production and ensuring global food security, particularly considering the challenges posed by population growth. In the present study, seven faba bean lines and four testers were used in a line×tester mating design during 2020-2021 and 2021-2022 growing seasons. The eleven parents and their 28 F1 crosses were evaluated under Orobanche free and naturally infested soils. RESULTS: The results demonstrated considerable variations among the evaluated genotypes, wide diversity among the parental materials, and heterotic effects for all studied agronomic traits under Orobanche-free and infested soils. Orbanche infestation displayed a significant adverse impact on all the studied agronomic traits. The genotypes Line1, Line2, Line3, and Line5 displayed superior performance under Orobanche-infested conditions and recorded the highest values of all studied agronomic traits. Additionally, Line1, Line2, Line3, Line5, and Line7 exhibited desirable significant GCA for most evaluated traits under the two infestation conditions. The obtained crosses displayed significant negative or positive heterosis for studied agronomic characters such as plant height, number of branches per plant, number of pods per plant, number of seeds per plant, and seed weight per plant were observed. Furthermore, specific cross combinations such as Line2×Sakha3, Line3×Nubaria5, Line7 × Nubaria5, Line6×Nubaria1, Line5×Sakha3, Line1×Sakha3, and Line1 × Nubaria5 exhibited superior performance in seed yield and contributing traits under Orobanche-infested conditions. Moreover, these specific crosses showed superior efficacy in reducing dry weight of Orobanche spikes. The results obtained from GGE biplot analysis closely aligned with those from the line×tester procedure, affirming the significance of GGE biplot as a valuable statistical tool for assessing genotype combining ability in line× tester data. Both additive and non-additive gene actions were reported to be predominantly involved in the inheritance of the studied agronomic traits in faba bean. CONCLUSIONS: The detected genetic diversity within the evaluated faba bean genotypes and their developed crosses exhibits substantial potential for improving faba bean productivity under Orobanche-infested conditions. The parental genotypes, Line1, Line2, Line3, Line5, and Line7, were identified as effective and promising combiners. Moreover, the developed crosses Line2×Sakha3, Line3×Nubaria5, Line7×Nubaria5, Line6×Nubaria1, Line5×Sakha3, Line1×Sakha3, and Line1×Nubaria5 could be considered valuable candidates for developing high-yielding and tolerant faba bean genotypes to Orobanche.

FecB Was Associated with Litter Size and Follows Mendel's Laws of Inheritance When It Transited to Next Generation in Suhu Meat Sheep Breeding Population.

In order to investigate the effect of FecB on litter size and growth and development traits of Suhu meat sheep and the inheritance patterns of FecB between parents and offspring in the population. In this experiment, 2241 sheep from the Suhu meat sheep population were tested for FecB using capillary electrophoresis. We combined the lambing records of 473 ewes, the growth trait records of 881 sheep at both the birth and weaning (2-month-old) stages, and the complete genealogical records of 643 lambs to analysis the distribution of FecB in the Suhu meat sheep breeding population, its effect on litter size of ewes, growth and development of lambs, and the inheritance patterns of FecB. The results showed that there were three genotypes of FecB in the Suhu meat sheep population, namely the AA genotype, AG genotype, and GG genotype. FecB in this population has a moderate polymorphism (0.25 < PIC < 0.5), and deviates from Hardy-Weinberg disequilibrium (p < 0.05). The litter size of GG genotype ewes was significantly higher than that with the AG and AA genotypes (p < 0.01). A Chi-square test showed that the inheritance patterns of FecB follows Mendel's Laws of Inheritance (p > 0.05). An association analysis of different genotypes of FecB with body weight and body size of Suhu meat sheep at birth and weaning revealed that FecB adversely affects the early growth and development of Suhu meat sheep. In summary, FecB can improve the litter size of ewes but it has negative effects on the early growth and survival rate of lambs in sheep. Therefore, FecB test results and feeding management measures should be comprehensively applied to improve the reproductive performance of ewes, the survival rate and production performance of lambs in sheep production, and thus improve the economic benefits of sheep farms.

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Calling the question: what is mammalian transgenerational epigenetic inheritance?

While transgenerational epigenetic inheritance has been extensively documented in plants, nematodes, and fruit flies, its existence in mammals remains controversial. Several factors have contributed to this debate, including the lack of a clear distinction between intergenerational and transgenerational epigenetic inheritance (TEI), the inconsistency of some studies, the potential confounding effects of in-utero vs. epigenetic factors, and, most importantly, the biological challenge of epigenetic reprogramming. Two waves of epigenetic reprogramming occur: in the primordial germ cells and the developing embryo after fertilization, characterized by global erasure of DNA methylation and remodelling of histone modifications. Consequently, TEI can only occur if specific genetic regions evade this reprogramming and persist through embryonic development. These challenges have revived the long-standing debate about the possibility of inheriting acquired traits, which has been strongly contested since the Lamarckian and Darwinian eras. As a result, coupled with the absence of universally accepted criteria for transgenerational epigenetic studies, a vast body of literature has emerged claiming evidence of TEI. Therefore, the goal of this study is to advocate for establishing fundamental criteria that must be met for a study to qualify as evidence of TEI. We identified five criteria based on the consensus of studies that critically evaluated TEI. To assess whether published original research papers adhere to these criteria, we examined 80 studies that either claimed or were cited as supporting TEI. The findings of this analysis underscore the widespread confusion in this field and highlight the urgent need for a unified scientific consensus on TEI requirements.

Accurate phenotypic self-replication as a necessary cause for biological evolution.

Since the Origin of Species, it has been known that evolution depends on what Darwin called the "strong principle of inheritance." Highly accurate replication of cellular phenotype is a universal phenomenon in all of life since LUCA and is often taken for granted as a constant in evolutionary theory. It is not known how self-replication arose during the origin of life. In this report I use the simple mathematics of evolutionary theory to investigate the dynamics of self-replication accuracy and allelic selection. Results indicate that the degree of self-replication accuracy must be greater than a threshold related to the selection coefficients of the alleles in a population in order for evolution to occur. Accurate replication of cellular phenotype and of the molecules involved in genotype/phenotype linkage is necessary for the origin of evolution and may be considered the fundamental principle of life.

Genetic confounds of transgenerational epigenetic inheritance in mice.

Transgenerational epigenetic inheritance in mammals remains a controversial phenomenon. A recent study by Takahashi et al. provides evidence for this mode of inheritance in mice by using a CRISPR/Cas9-based epigenetic editing technique to modify DNA methylation levels at specific promoters and then demonstrating the inheritance of the gain in methylation in offspring. In this technical commentary, we argue that the method used in the original study inherently amplifies the likelihood of genetic changes that thereafter lead to the heritability of epigenetic changes. We provide evidence that genetic changes from multiple sources do indeed occur in these experiments and explore several avenues by which these changes could be causal to the apparent inheritance of epigenetic changes. We conclude a genetic basis of inheritance cannot be ruled out and thus transgenerational epigenetic inheritance has not been adequately established by the original study.

Inheritance of feed intake-based resilience traits and their correlation with production traits in Finnish pig breeds.

High resilience against diseases, changing environmental conditions, and other stress factors and the ability to efficiently recover to normal status, is becoming increasingly important in pig production. Finding new phenotypes that relate to resilience is a crucial step for improving the resilience of pigs through selection. The objective of this study was to extract resilience-related phenotypes based on fluctuations in daily feed intake (DFI, g) and time spent in feeding per day (TPD, min) and to estimate the heritability of these traits and genetic correlations with production traits (PT). Resilience-related traits with high enough heritability and with either favorable or neutral genetic correlation with PT could be used in the selection program to improve the productivity and welfare of pigs. In this study, we used data from 7,347 Finnish Yorkshire, Landrace, and crossbred pigs raised at the test station. Six pig-specific resilience-related phenotypes were extracted from the individual DFI and TPD: root mean square error (RMSE), quantile regression (QR), and coefficient of variation (CV). RMSE was calculated from the differences between the actual DFI (or TPD) and the pig-specific predicted values. QR was based on the number of days that a pig belonged to the group with the lowest 5% of pigs based on DFI (or TPD), and CV was calculated over the daily observations of DFI (or TPD). PT included average daily gain (ADG, g), backfat thickness (BF, mm), and feed conversion rate (FCR, g/g). The heritability estimates for resilience-related traits varied between 0.07 ±â€…0.02 (QRDFI) and 0.20 ±â€…0.03 (RMSETPD). The genetic correlations between resilience-related traits and PT were mostly neutral, but for example, RMSEDFI had a favorable genetic correlation with FCR and BF but an unfavorable correlation with ADG. Lastly, we observed that pigs belonging to the lowest 10% group based on their breeding value (BV) for QRTPD had a lower proportion (10% incidence) of sick days compared to the highest 10% BV group (30% incidence). Therefore, pigs exhibiting small TPD variation (related to high resilience) tend to be less susceptible to sickness than pigs with large TPD variation (related to low resilience). Given its moderate heritability, neutral genetic correlation with PT, and positive effect on health, QRTPD can be considered the most promising resilience-related trait in the Finnish production system.

Improving resilience, i.e., the capacity to respond to the impacts of stressors and to effectively recover to normal status, is a promising approach to enhancing the well-being of pigs and the productivity of the pig industry. Animals with high resilience can maintain their performance under challenging conditions. However, obtaining heritable measurements and indicators of resilience is challenging. One indicator of resilience is fluctuation in daily feed intake (DFI) and time spent in feeding per day (TPD). In our study, the proportion of days during which a particular pig belongs to the lowest 5% of pigs based on TPD (QRTPD) turned out to be the most promising resilience-related trait. This trait is moderately inheritable and has only a weak genetic correlation with production traits (PTs). Pigs with the most favorable breeding values (BVs) for QRTPD had four times fewer sick days than pigs with less favorable BVs for QRTPD. Overall, selecting QRTPD would improve pig resilience and health without negative effects on PTs.

OcBSA: An NGS-based bulk segregant analysis tool for outcross populations.

Constructing inbred lines for self-incompatible species and species with long generation times is challenging, making the use of F1 outcross/segregating populations the main strategy for genetic studies of such species. However, there is a lack of dedicated algorithms/tools for rapid quantitative trait locus (QTL) mapping using the F1 populations. To this end, we have designed and developed an algorithm/tool called OcBSA specifically for QTL mapping of F1 populations. OcBSA transforms the four-haplotype inheritance problem from the two heterozygous diploid parents of the F1 population into the two-haplotype inheritance problem common in current genetic studies by removing the two haplotypes from the heterozygous parent that do not contribute to phenotype segregation in the F1 population. Testing of OcBSA on 1800 simulated F1 populations demonstrated its advantages over other currently available tools in terms of sensitivity and accuracy. In addition, the broad applicability of OcBSA was validated by QTL mapping using seven reported F1 populations of apple, pear, peach, citrus, grape, tea, and rice. We also used OcBSA to map the QTL for flower color in a newly constructed F1 population of potato generated in this study. The OcBSA mapping result was verified by the insertion or deletion markers to be consistent with a previously reported locus harboring the ANTHOCYANIN 2 gene, which regulates potato flower color. Taken together, these results highlight the power and broad utility of OcBSA for QTL mapping using F1 populations and thus a great potential for functional gene mining in outcrossing species. For ease of use, we have developed both Windows and Linux versions of OcBSA, which are freely available at: https://gitee.com/Bioinformaticslab/OcBSA.

The Pathophysiology of Inherited Renal Cystic Diseases.

Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment.

Protocol to study the inheritance and propagation of non-genetically encoded states using barcode decay lineage tracing.

Here, we present a protocol to perform barcode decay lineage tracing followed by single-cell transcriptome analysis (BdLT-Seq). We describe steps for BdLT-Seq experimental design, building barcoded episome reporters, performing episome transfection, and barcode retrieval. We then describe procedures for sequencing library construction while providing options for sample multiplexing and data analysis. This BdLT-Seq technique enables the assessment of clonal evolution in a directional manner while preserving isogeneity, thus allowing the comparison of non-genetic molecular features between isogenic cell lineages. For complete details on the use and execution of this protocol, please refer to Shlyakhtina et al. (2023).1.

Data from electronic healthcare records expand our understanding of X-linked genetic diseases.

Disease specific cohort studies have reported details on X linked (XL) disorders affecting females. We investigated the spectrum and penetrance of XL disorders seen in electronic health records (EHR). We generated a cohort of individuals diagnosed with XL disorders at Vanderbilt University Medical Center over 20 years. Our cohort included 477 males and 203 females diagnosed with 108 different XL genetic disorders. We found large differences between the female/male (F/M) ratios for various XL disorders regardless of their OMIM annotated mode of inheritance. We identified four XL recessive disorders affecting women previously only described in men. Biomarkers for XL disease had unique gender-specific patterns differing between modes of inheritance. EHRs provide large cohorts of XL genetic disorders that give new insights compared to the literature. Differences in the F/M ratios and biomarkers of XL disorders observed likely result from disease specific and sex dependent penetrance. We conclude that observed gender ratios associated with specific XL disorders may be more useful than those predicted by Mendelian genetics provided by OMIM. Our findings of a gender specific penetrance and severity for XL disorders show unexpected differences from Mendelian predictions. Further work is required to validate our findings in larger combined EHR cohorts.

Autosomal recessive intellectual disability caused by compound heterozygous variants of the EEF1D gene in a Chinese family.

BACKGROUND: Intellectual disability is a prevalent neurodevelopmental disorder, with the majority of affected children exhibiting global developmental delay before the age of 5 years. In recent years, certain children have been found to carry homozygous variations of the EEF1D gene, leading to autosomal recessive intellectual disability. However, the pathogenicity of compound heterozygous variations in this gene remains largely unknown. METHODS: Trio whole-exome sequencing and copy number variation sequencing were done for the genetic etiological diagnosis of a 3-year and 11-month-old Chinese boy who presented with brachycephaly, severe to profound global developmental delay, and hypotonia in the lower limbs. RESULTS: In this case, compound heterozygous variants of the EEF1D gene were found in the child through trio whole-exome sequencing; one was a splice variant (NM_032378.6:c.1905+1G>A) inherited from his father, and the other was a nonsense variant (NM_032378.6:c.676C>T) inherited from his mother. The nonsense variant leads to the production of a premature termination (p.Gln226*). These variations have the ability to explain the clinical phenotypes of the child. CONCLUSIONS: Our study expands the variation spectrum and provides compelling evidence for EEF1D as a candidate gene for autosomal recessive intellectual disability. However, due to the deficient number of reported cases, researchers need to further study EEF1D and supplement the clinical phenotypes and treatment measures.

Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis.

Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information on long-term outcomes remains poor. We present the long-term outcomes (median, 19 years) of nine patients with alpha-mannosidosis, three females and six males, followed at a single center. The findings of the nine patients were collected from medical records and reported as mean ± SD or median, and range. The age of onset of the first symptoms ranged from 0-1 to 10 years. The diagnostic delay ranged from 2 to 22 years (median= 11 years). Coarse face, hearing, heart valves, joints, gait, language, dysarthria, psychiatric symptoms, I.Q., MRI, walking disabilities, orthopedic disturbances and surgeries showed a slow worsening over the decades. Our patients showed a slowly worsening progressive outcome over the decades. Psychiatric symptoms were present in 100% of our population and improved with the appropriate pharmacological intervention. This aspect requires attention when following up on these patients. Our description of the long-term evolution of alpha-mannosidosis patients may provide basic knowledge for understanding the effects of specific treatments.

Paternal leakage of plastids rescues inter-lineage hybrids in Silene nutans.

BACKGROUND AND AIMS: Organelle genomes are usually maternally inherited in angiosperms. However, biparental inheritance has been observed, especially in hybrids resulting from crosses between divergent genetic lineages. When it concerns the plastid genome, this exceptional mode of inheritance might rescue inter-lineage hybrids suffering from plastid-nuclear incompatibilities. Genetically differentiated lineages of Silene nutans exhibit strong postzygotic isolation owing to plastid-nuclear incompatibilities, highlighted by inter-lineage hybrid chlorosis and mortality. Surviving hybrids can exhibit variegated leaves, which might indicate paternal leakage of the plastid genome. We tested whether the surviving hybrids inherited the paternal plastid genome and survived thanks to paternal leakage. METHODS: We characterized the leaf phenotype (fully green, variegated or white) of 504 surviving inter-lineage hybrids obtained from a reciprocal cross experiment among populations of four genetic lineages (W1, W2, W3 and E1) of S. nutans from Western Europe and genotyped 560 leaf samples (both green and white leaves for variegated hybrids) using six lineage-specific plastid single nucleotide polymorphisms. KEY RESULTS: A high proportion of the surviving hybrids (≤98 %) inherited the paternal plastid genome, indicating paternal leakage. The level of paternal leakage depended on cross type and cross direction. The E1 and W2 lineages as maternal lineages led to the highest hybrid mortality and to the highest paternal leakage from W1 and W3 lineages in the few surviving hybrids. This was consistent with E1 and W2 lineages, which contained the most divergent plastid genomes. When W3 was the mother, more hybrids survived, and no paternal leakage was detected. CONCLUSIONS: By providing a plastid genome potentially more compatible with the hybrid nuclear background, paternal leakage has the potential to rescue inter-lineage hybrids from plastid-nuclear incompatibilities. This phenomenon might slow down the speciation process, provided hybrid survival and reproduction can occur in the wild.

Loss of NDST1 N-sulfotransferase activity is associated with autosomal recessive intellectual disability.

Intellectual Disability (ID) is the major cause of handicap, affecting nearly 3% of the general population, and is highly genetically heterogenous with more than a thousand genes involved. Exome sequencing performed in two independent families identified the same missense variant, p.(Gly611Ser), in the NDST1 (N-deacetylase/N-sulfotransferase member 1) gene. This variant had been previously found in ID patients of two other families but has never been functionally characterized. The NDST1 gene encodes a bifunctional enzyme that catalyzes both N-deacetylation and N-sulfation of N-acetyl-glucosamine residues during heparan sulfate (HS) biosynthesis. This step is essential because it influences the downstream enzymatic modifications and thereby determines the overall structure and sulfation degree of the HS polysaccharide chain. To discriminate between a rare polymorphism and a pathogenic variant, we compared the enzymatic properties of wild-type and mutant NDST1 proteins. We found that the p.(Gly611Ser) variant results in a complete loss of N-sulfotransferase activity while the N-deacetylase activity is retained. NDST1 shows the highest and the most homogeneous expression in the human cerebral structures compared to the other members of the NDST gene family. These results indicate that a loss of NDST1 N-sulfation activity is associated with impaired cognitive functions.

Diversity and Classification of Genetic Variations in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with symptoms that affect the whole personality and all aspects of life. Although there is a high degree of heterogeneity in both its etiology and its characteristic behavioral patterns, the disorder is well-captured along the autistic triad. Currently, ASD status can be confirmed following an assessment of behavioral features, but there is a growing emphasis on conceptualizing autism as a spectrum, which allows for establishing a diagnosis based on the level of support need, free of discrete categories. Since ASD has a high genetic predominance, the number of genetic variations identified in the background of the condition is increasing exponentially as genetic testing methods are rapidly evolving. However, due to the huge amount of data to be analyzed, grouping the different DNA variations is still challenging. Therefore, in the present review, a multidimensional classification scheme was developed to accommodate most of the currently known genetic variants associated with autism. Genetic variations have been grouped according to six criteria (extent, time of onset, information content, frequency, number of genes involved, inheritance pattern), which are themselves not discrete categories, but form a coherent continuum in line with the autism spectrum approach.

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

BACKGROUND: Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. METHODS: In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience Sequel IIe platform. RESULTS: Likely causal variants were identified in 13 (38%) of the cohort. These include (1) a homozygous splicing SV in TYMS as a novel candidate gene for lethal neonatal lactic acidosis, (2) a homozygous non-coding SV that we propose impacts STK25 expression and causes a novel neurodevelopmental disorder, (3) a compound heterozygous SV in RP1L1 with complex inheritance pattern in a family with inherited retinal disease, (4) homozygous deep intronic variants in LEMD2 and SNAP91 as novel candidate genes for neurodevelopmental disorders in two families, and (5) a promoter SNV in SLC4A4 causing non-syndromic band keratopathy. Surprisingly, we also encountered causal variants that could have been identified by short-read exome sequencing in 7 families. The latter highlight scenarios that are especially challenging at the interpretation level. CONCLUSIONS: Our data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility.