Search Results (30)

Background/Objectives: Dense genetic marker panels are increasingly used in kinship analysis for the identification of distant relatives. As more markers are available, it is possible to pinpoint IBD segments more precisely and more reliably, ultimately approaching close to continuously observed IBD. This study investigates the evidential value obtained for discrimination between common pedigree relationships if IBD is observed continuously across the autosomal genome without error. In the continuous case, the evidential value is limited only by the pedigree relationship and the recombination rates. Methods: We conducted simulations to generate IBD segments across the autosomal genome for individuals with defined pedigree relationships. The evidential value for relationship discrimination was then calculated exactly from the underlying model, assuming no genotyping error and full genome coverage. Results: The simulations show that the ability to distinguish pedigree relationships quickly diminishes as relationships become more distant. First cousins can be distinguished from second cousins with 99.9% accuracy which drops to 94% when distinguishing second and third cousins. Relationships with the same expected degree of relatedness can be discriminated using continuously observed IBD, although the effectiveness decreases with more distant relationships. Conclusions: Continuous IBD observation establishes a theoretical upper bound on the power to distinguish relationships if a large but finite number of markers is used. The findings provide a benchmark for evaluating kinship analyses based on finite genetic marker panels. Full article

The children born of consanguineous union were found to have a higher incidence of recessive genetic diseases than the offspring of unrelated parents. The reason for this was predicted to be the presence of more deleterious rare homozygous genetic variants in the former compared to the latter. However, the magnitude of this difference is unknown. Using more than 2500 whole genomes, we show here that the individuals born of the union between double (paternal and maternal) first cousins had 20 times more deleterious rare homozygous single nucleotide variants (SNVs) than those who had unrelated parents. Furthermore, the children of first cousins had 10 times, and the children of second cousins had two times more of these SNVs compared to those present in the offspring of unrelated parents. Similar magnitudes of differences were found for the nonsynonymous deleterious rare homozygous SNVs (19, 10, and 2 times, respectively). In contrast, the differences in the number of deleterious low-frequency and common homozygous variants between the children of cousins and those of unrelated parents were 1–3 times and 1–7%, respectively. These results suggest that the offspring of consanguineous union could have a 20 times higher risk of recessive autosomal diseases caused by rare variants. Conversely, consanguinity appears to have little effect on the risk of common diseases. These findings have implications for future clinical research in identifying genetic variants associated with inherited diseases. Furthermore, the magnitude of the elevated risk revealed in this study could be useful in genetic counseling and for public health in creating awareness. Full article

Background and Clinical Significance: Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders consisting of mutations of hepatocyte transporting-system genes involved in bile formation. The exact prevalence remains unknown but is estimated at 1 in 500.000 for PFIC 3, caused by mutations in the ABCB4 gene. We report three cases of PFIC 3 from the patient’s sister, brother, and cousin, diagnosed in our Pediatric Department in 2022–2023. Case Presentation: Case 1: A 10-year-old girl was admitted for jaundice and abdominal pain. She was diagnosed with severely advanced hepatic cirrhosis and massive cholestasis. Genetic testing showed ABCB4 homozygous mutation. She rapidly developed fulminant liver failure, and a living donor liver transplant was performed. Case 2: A 6-year-old brother was previously diagnosed with cholestatic hepatitis of unknown cause back in 2018 and presented with similar features (generalized jaundice, severe pruritus with generalized scratching lesions); symptoms had progressively developed from the first year of life. He also exhibited particular facial features (big forehead, twisted ear lobe, straight nose). He received cadaveric liver transplantation. Case 3: Nephew of first two children, a 3-year-5-month-old boy, was admitted for failure to thrive and a one-year history of jaundice, pruritus, and splenomegaly. He was tested positive for homozygous ABCB4 mutation. He is currently under medical treatment with stable liver function. Conclusions: The clinical significance of this particular homozygous variant identified in ABCB4 in our series of cases (c.2534G>T (p.Gly845Val)) was uncertain up to this case report. The present data provide convincing evidence as to the correlation between this mutation and the clinical phenotype of PFIC 3. Full article

Crop phenotype detection is a precise way to understand and predict the growth of horticultural seedlings in the smart agriculture era to increase the cost-effectiveness and energy efficiency of agricultural production. Crop phenotype detection requires the consideration of plant stature and agricultural devices, like robots and autonomous vehicles, in smart greenhouse ecosystems. However, collecting the imaging dataset is a challenge facing the deep learning detection of plant phenotype given the dynamic changes among leaves and the temporospatial limits of camara sampling. To address this issue, digital cousin is an improvement on digital twins that can be used to create virtual entities of plants through the creation of dynamic 3D structures and plant attributes using RGB image datasets in a simulation environment, using the principles of the variations and interactions of plants in the physical world. Thus, this work presents a two-phase method to obtain the phenotype of horticultural seedling growth. In the first phase, 3D Gaussian splatting is selected to reconstruct and store the 3D model of the plant with 7000 and 30,000 training rounds, enabling the capture of RGB images and the detection of the phenotypes of the seedlings, overcoming temporal and spatial limitations. In the second phase, an improved YOLOv8 model is created to segment and measure the seedlings, and it is modified by adding the LADH, SPPELAN, and Focaler-ECIoU modules. Compared with the original YOLOv8, the precision of our model is 91%, and the loss metric is lower by approximately 0.24. Moreover, a case study of watermelon seedings is examined, and the results of the 3D reconstruction of the seedlings show that our model outperforms classical segmentation algorithms on the main metrics, achieving a 91.0% mAP50 (B) and a 91.3% mAP50 (M). Full article

Adenylate cyclase 3 (ADCY3) is a transmembrane protein predominantly expressed in the primary cilia of neurons. It plays a vital role in converting ATP to cAMP, a secondary messenger that regulates various downstream signaling pathways such as carbohydrates and lipids metabolism. Homozygous loss-of-function variants in the ADCY3 gene lead to severe early-onset obesity and insulin resistance whereas gain-of-function variants protect against obesity. To describe a novel pathogenic ADCY3 variant implicated in early-onset obesity and functionally characterize this variant via in vitro and in silico validation, we identified a novel homozygous nonsense variant c.2520C>G, p.Thr840X in the ADCY3 gene using gene panel sequencing in a four-year-old girl. She was born to first-cousin consanguineous parents. The patient presented with severe obesity, and exhibited hepatomegaly and insulin resistance, with other biochemical and hormonal tests being normal. In vitro and in silico functional analyses showed downregulation and impaired activation of the ADCY3 protein. Our findings contribute to existing research that supports the role of ADCY3 in the genetic pathogenesis of early-onset obesity. In vitro and in silico functional characterization of the novel p.Thr840X variant showed impaired enzymatic activity leading to receptor loss of function, consistent with the patient’s phenotype. Genetic testing is essential in severe early-onset obesity and early diagnosis could benefit patients with personalized treatment strategies. Full article

Additive friction stir deposition (AFSD) is a solid-state metal additive manufacturing technique, which utilizes frictional heating and plastic deformation to create large deposits and parts. Much like its cousin processes, friction stir welding and friction stir processing, AFSD has seen the most compatibility and use with lower-temperature metals, such as aluminum; however, there is growing interest in higher-temperature materials, such as titanium and steel alloys. In this work, we explore the deposition of an ultrahigh-temperature refractory material, specifically, a tantalum–tungsten (TaW) alloy. The solid-state nature of AFSD means refractory process temperatures are significantly lower than those for melt-based additive manufacturing techniques; however, they still pose difficult challenges, especially in regards to AFSD tooling. In this study, we perform initial deposition trials of TaW using twin-rod-style AFSD with a high-temperature tungsten–rhenium-based tool. Many challenges arise because of the high temperatures of the process and high mechanical demand on AFSD machine hardware to process the strong refractory alloy. Despite these challenges, successful deposits of the material were produced and characterized. Mechanical testing of the deposited material shows improved yield strength over that of the annealed reference material, and this strengthening is mostly attributed to the refined recrystallized microstructure typical of AFSD. These findings highlight the opportunities and challenges associated with ultrahigh-temperature AFSD, as well as provide some of the first published insights into twin-rod-style AFSD process behaviors. Full article

Andersen–Tawil syndrome (ATS) is a multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, prolonged QT interval, and facial dysmorphisms occurring in the first/second decade of life. High phenotypic variability and incomplete penetrance of the genes causing the disease make its diagnosis still a challenge. We describe a three-generation family with six living individuals affected by ATS. The proband is a 37-year-old woman presenting since age 16, with episodes of muscle weakness and cramps in the pre-menstrual period. The father, two brothers, one paternal uncle and one cousin also complained of cramps, muscle stiffness, and weakness. Despite normal serum potassium concentration, treatment with potassium, magnesium, and acetazolamide alleviated paralysis attacks suggesting a dyskalemic syndrome. Dysmorphic features were noted in the proband, only later. On the ECG, all but one had normal QT intervals. The affected males developed metabolic syndrome or obesity. The father had two myocardial infarctions and was implanted with an intracardiac cardioverter defibrillator (ICD). A genetic investigation by WES analysis detected the heterozygous pathogenic variant (NM_000891.2: c.652C>T, p. Arg218Trp) in the KCNJ2 gene related to ATS, confirmed by segregation studies in all affected members. Furthermore, we performed a review of cases with the same mutation in the literature, looking for similarities and divergences with our family case. Full article

Microhaplotypes (MHs) consisting of multiple SNPs and indels on short stretches of DNA are new and interesting loci for forensic genetic investigations. In this study, we analysed 74 previously defined MHs in two of the populations that our laboratory provides with forensic genetic services, Danes and Greenlanders. In addition to the 229 SNPs that originally made up the 74 MHs, 66 SNPs and 3 indels were identified in the two populations, and 45 of these variants were included in new definitions of the MHs, whereas 24 SNPs were considered rare and of little value for case work. The average effective number of alleles (A_e) was 3.2, 3.0, and 2.6 in Danes, West Greenlanders, and East Greenlanders, respectively. High levels of linkage disequilibrium were observed in East Greenlanders, which reflects the characteristics of this population that has a small size, and signs of admixture and substructure. Pairwise kinship simulations of full siblings, half-siblings, first cousins, and unrelated individuals were performed using allele frequencies from MHs, STRs and SNPs from Danish and Greenlandic populations. The MH panel outperformed the currently used STR and SNP marker sets and was able to differentiate siblings from unrelated individuals with a 0% false positive rate and a 1.1% false negative rate using an LR threshold of 10,000 in the Danish population. However, the panel was not able to differentiate half-siblings or first cousins from unrelated individuals. The results generated in this study will be used to implement MHs as investigative markers for relationship testing in our laboratory. Full article

Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)⁻⁵] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1–3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia. Full article

Consanguineous marriage (CM) is a prevalent kind of relationship in Muslim and Arab countries, and this type of relationship is linked to several health risks. This study was conducted to determine the prevalence of (CM), its associated hereditary diseases, and health-related issues among Saudi citizens in Albaha. This cross-sectional study was conducted between March 2021 to April 2021. Saudi citizens in Albaha who were aged ≥ 18 years and willing to participate were eligible for the study. A total of 1010 participants were included in this study. In total, 757 participants were married, widowed, or divorced. CM partnerships comprised 40% (N = 302) of the marriages among participants, of which first- and second-cousin marriages comprised 72% and 28%, respectively. The prevalence of CM among the participants’ parents was lower than that among the participants (31% versus 40%, respectively). Children of participants in a CM were more likely to have cardiovascular diseases (p < 0.001), blood diseases (anaemia, thalassemia) (p < 0.001), cancer (p = 0.046), hearing loss and speech disorder (p = 0.003), and ophthalmic diseases (p = 0.037). Albaha showed a high percentage of consanguinity. An educational program must be established to enhance the population’s knowledge of the consequences of CM. The current national premarital screening program should be extended to involve more screening tests for common hereditary diseases that result from CM. Full article

Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund–Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer. Full article

Heterozygous pathogenic variants in DNM1 are linked to an autosomal dominant form of epileptic encephalopathy. Recently, homozygous loss-of-function variants in DNM1 were reported to cause an autosomal recessive form of developmental and epileptic encephalopathy in unrelated patients. Here, we investigated a singleton from a first-degree cousin marriage who presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. To identify the involvement of any likely genetic cause, diagnostic clinical exome sequencing was performed. Comprehensive filtering revealed a single plausible candidate variant in DNM1. Sanger sequencing of the trio, the patient, and her parents, confirmed the full segregation of the variant. The variant is a deletion leading to a premature stop codon and is predicted to cause a protein truncation. Structural modeling implicated a complete loss of function of the Dynamin 1 (DNM1). Such mutation is predicted to impair the nucleotide binding, dimer formation, and GTPase activity of DNM1. Our study expands the phenotypic spectrum of pathogenic homozygous loss-of-function variants in DNM1. Full article

We present two cases of family members (first cousins) with short extremities caused by a novel variant of COL2A1 gene (NM_001844.5). Case 1 description: A 29-year-old woman presented in her first pregnancy for a second trimester anomaly scan at 23 weeks of gestation. Fetal long bones were measured below the third centile for gestational age. Follow-up scans revealed fetal long bone growth deceleration. Initial genetic work-up was negative and the rest of the maternal follow-up was unremarkable. A male baby weighing 3180 g was delivered at 39 weeks and 4 days of gestation. Case 2 description: A 33-year-old pregnant woman presented for a routine second trimester anomaly scan at 20 weeks and 4 days of gestation. All fetal measurements were appropriate for the gestational age. The routine growth scan performed at 32 weeks showed fetal long bone measurements below the third centile for gestational age, while the follow-up growth scan at 36 weeks and 4 days of gestation revealed consistent, below the third centile, fetal long bone growth. Given that the fetuses of these two cases were related (first cousins), whole exome sequencing (WES) was performed on Case 2. WES revealed a novel heterozygous missense variant c.1132G>A (p. Gly378Ser) of COL2A1 gene (NM_001844.5). Subsequently, targeted genetic sequencing for the variant was performed on Case 1 and the same novel variant was found. Targeted sequencing revealed the same variant in the mother of Case 1 and the father of Case 2 (siblings). A female baby weighing 3200 g was delivered at 40 weeks and 4 days of gestation. Full article

Congenital heart disease (CHD) encompasses a wide range of structural defects of the heart and, in many cases, the factors that predispose an individual to disease are not well understood, highlighting the remarkable complexity of CHD etiology. Evidence of familial aggregation of CHD has been demonstrated in different communities and for different cardiac lesions. Consanguinity, particularly among first cousins, is an added risk factor for these families, particularly in societies where it is considered a common cultural practice, as confirmed in previous studies conducted in Saudi Arabia and other countries. Through comprehensive genetic testing of affected families, we have been able to better understand the genetic basis of the various cardiac lesions and to delineate the molecular mechanisms involved in cardiac morphogenesis. In this review, we discuss the epidemiology and genetics of CHD in consanguineous populations focusing on Saudi Arabia as an extensive study model to address current advances and challenges in the clinical genetic diagnosis and prevention of CHD. Full article

Dwarf galaxies are by far the most numerous galaxies in the Universe, showing properties that are quite different from those of their larger and more luminous cousins. This review focuses on the physical and chemical properties of the interstellar medium of those dwarfs that are known to host significant amounts of gas and dust. The neutral and ionized gas components and the impact of the dust will be discussed, as well as first indications for the existence of active nuclei in these sources. Cosmological implications are also addressed, considering the primordial helium abundance and the similarity of local Green Pea galaxies with young, sometimes protogalactic sources in the early Universe. Full article