[Analysis of a child with developmental disorder and epilepsy due to a homozygous variant of SLC25A12 gene].

OBJECTIVE: To explore the genetic basis for a child featuring global developmental delay and epilepsy. METHODS: A child who had presented at Guangzhou Women and Children's Medical Center Liuzhou Hospital on February 19, 2023 was selected as the study subject. Clinical data of the child was collected. The child was subjected to whole exome sequencing, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, an 8-month-old girl, had manifested with global developmental delay, epilepsy, and hyperlactacidemia. Cranial MRI revealed diverse hypomyelinating leukodystrophies. Electroencephalogram showed slow background activities. Genetic testing revealed that she has harbored a homozygous variant of the SLC25A12 gene, namely c.115T>G (p.Phe39Val), for which both of her parents were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be of uncertain significance (PM2_Supporting+PM3_Supporting+PP3_Moderate+PP4_Moderate). I-Mutant v3.0 software predicted that the variant may affect the stability of protein product. CONCLUSION: The homozygous c.115T>G (p.Phe39Val) variant of the SLC25A12 gene probably underlay the pathogenesis of the disease in this child.

A case of inherited glycosylphosphatidylinositol deficiency caused by PGAP3 variant with uniparental isodisomy on chromosome 17.

BACKGROUND: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. METHOD: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. RESULTS: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. CONCLUSION: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.

Identification of consensus homozygous regions and their associations with growth and feed efficiency traits in American mink.

The recent chromosome-based genome assembly and the newly developed 70K single nucleotide polymorphism (SNP) array for American mink (Neogale vison) facilitate the identification of genetic variants underlying complex traits in this species. The objective of this study was to evaluate the association between consensus runs of homozygosity (ROH) with growth and feed efficiency traits in American mink. A subsample of two mink populations (n = 2,986) were genotyped using the Affymetrix Mink 70K SNP array. The identified ROH segments were included simultaneously, concatenated into consensus regions, and the ROH-based association studies were carried out with linear mixed models considering a genomic relationship matrix for 11 growth and feed efficiency traits implemented in ASReml-R version 4. In total, 298,313 ROH were identified across all individuals, with an average length and coverage of 4.16 Mb and 414.8 Mb, respectively. After merging ROH segments, 196 consensus ROH regions were detected and used for genome-wide ROH-based association analysis. Thirteen consensus ROH regions were significantly (P < 0.01) associated with growth and feed efficiency traits. Several candidate genes within the significant regions are known for their involvement in growth and body size development, including MEF2A, ADAMTS17, POU3F2, and TYRO3. In addition, we found ten consensus ROH regions, defined as ROH islands, with frequencies over 80% of the population. These islands harbored 12 annotated genes, some of which were related to immune system processes such as DTX3L, PARP9, PARP14, CD86, and HCLS1. This is the first study to explore the associations between homozygous regions with growth and feed efficiency traits in American mink. Our findings shed the light on the effects of homozygosity in the mink genome on growth and feed efficiency traits, that can be utilized in developing a sustainable breeding program for mink.

Using high-density SNP data to unravel the origin of the Franches-Montagnes horse breed.

BACKGROUND: The Franches-Montagnes (FM) is the last native horse breed of Switzerland, established at the end of the 19th century by cross-breeding local mares with Anglo-Norman stallions. We collected high-density SNP genotype data (Axiom™ 670 K Equine genotyping array) from 522 FM horses, including 44 old-type horses (OF), 514 European Warmblood horses (WB) from Sweden and Switzerland (including a stallion used for cross-breeding in 1990), 136 purebred Arabians (AR), 32 Shagya Arabians (SA), and 64 Thoroughbred (TB) horses, as introgressed WB stallions showed TB origin in their pedigrees. The aim of the study was to ascertain fine-scale population structures of the FM breed, including estimation of individual admixture levels and genomic inbreeding (FROH) by means of Runs of Homozygosity. RESULTS: To assess fine-scale population structures within the FM breed, we applied a three-step approach, which combined admixture, genetic contribution, and FROH of individuals into a high-resolution network visualization. Based on this approach, we were able to demonstrate that population substructures, as detected by model-based clustering, can be either associated with a different genetic origin or with the progeny of most influential sires. Within the FM breed, admixed horses explained most of the genetic variance of the current breeding population, while OF horses only accounted for a small proportion of the variance. Furthermore, we illustrated that FM horses showed high TB admixture levels and we identified inconsistencies in the origin of FM horses descending from the Arabian stallion Doktryner. With the exception of WB, FM horses were less inbred compared to the other breeds. However, the relatively few but long ROH segments suggested diversity loss in both FM subpopulations. Genes located in FM- and OF-specific ROH islands had known functions involved in conformation and behaviour, two traits that are highly valued by breeders. CONCLUSIONS: The FM remains the last native Swiss breed, clearly distinguishable from other historically introgressed breeds, but it suffered bottlenecks due to intensive selection of stallions, restrictive mating choices based on arbitrary definitions of pure breeding, and selection of rare coat colours. To preserve the genetic diversity of FM horses, future conservation managements strategies should involve a well-balanced selection of stallions (e.g., by integrating OF stallions in the FM breeding population) and avoid selection for rare coat colours.

Trichohepatoenteric syndrome type 1: expanding the clinical spectrum of THES type 1 due to a homozygous variant in the SKIC3 gene.

Trichohepatoenteric syndrome (THES), also known as phenotypic diarrhea or syndromic diarrhea, is a rare autosomal recessive genetic disorder caused by mutations in SKIC2 (THES-type 2) or SKIC3 (THES-type 1) and is characterized by early onset diarrhea, woolly brittle hair, facial dysmorphic features and liver disease. We report the case of a 24-month-old girl who presented with chronic diarrhea since the neonatal period along with intrauterine growth restriction (IUGR), developmental delay, dysmorphic features, congenital heart defects, liver disease, and recurrent infections. The diagnosis was made through whole-exome sequencing analysis, which detected a homozygous variant (c.4070del, p.Pro1357Leufs*10) in the SKIC3 gene. The patient required parenteral nutrition and was hospitalized for the first 10 months of life and then discharged on PN after showing improvement. She remained stable on PN after discharge despite a few admissions for central line infections. Recent follow-up at the age of 2 years revealed that she was stable on long-term parenteral nutrition and that she had advanced chronic liver disease.

Multiple Thromboembolic Events in Young Patient with Homozygous T-786C Mutation in the Endothelial Nitric Oxide Synthase Gene (ENOS).

Thromboembolic events are a common cause of morbidity and mortality with significant socioeconomic impact especially when young patients are affected. They are a rare medical event in young people and their clinical presentation can be mild or asymptomatic. The manifestation of symptoms and thrombotic events depends on both: the genetic mutations and the external risk factors that will induce the process. We present a case of a 34-year old young female, with three consecutive cerebrovascular insults in a period of ten years, and an acute myocardial infarction. There is a combination of gene mutations and polymorphism, with a predisposition to thromboembolic events. We emphasized the role of e-NOS (Endothelial nitric oxide synthase 786 T>C mutation) and the connection with smoking. The dual effect of the prolonged smoking and dysfunctional nitric oxide synthase in our young patient led to several thrombotic events. We discussed the various diagnostic tests and possible therapeutic and prophylactic strategies.

HFE and Non-HFE Hereditary Hemochromatosis Based on Screening of 854 Individuals: 12 Years of an Iranian Experience.

Introduction: The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as "suspected cases of HH," to a diagnostic laboratory in Iran over a 12-year period. Materials and Methods: From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of HFE exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the HFE, TFR2, and FPN1(SLC40A1) genes and 733 cases were screened using this method. Results: From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for HFE:C282Y and five homozygotes for TFR2:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other HFE variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). Conclusion: This study showed that the spectrum of genetic variants of HH in the Iranian population includes HFE and TFR2 variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue.

Insights into the genomic homogeneity of Moroccan indigenous sheep breeds though the lens of runs of homozygosity.

Numerous studies have indicated that Morocco's indigenous sheep breeds are genetically homogenous, posing a risk to their survival in the challenging harsh climate conditions where they predominantly inhabit. To understand the genetic behind genetic homogeneity through the lens of runs of homozygosity (ROH), we analyzed the whole genome sequences of five indigenous sheep breeds (Beni Guil, Ouled Djellal, D'man, Sardi, Timahdite and Admixed).The results from principal component, admixture, Fst, and neighbour joining tree analyses consistently showed a homogenous genetic structure. This structure was characterized by an average length of 1.83 Mb for runs of homozygosity (ROH) segments, with a limited number of long ROH segments (24-48 Mb and > 48 Mb). The most common ROH segments were those ranging from 1-6 Mb. The most significant regions of homozygosity (ROH Islands) were mostly observed in two chromosomes, namely Chr1 and Chr5. Specifically, ROH Islands were exclusively discovered in the Ouled Djellal breed on Chr1, whereas Chr5 exhibited ROH Islands in all breeds. The analysis of ROH Island and iHS technique was employed to detect signatures of selection on Chr1 and Chr5. The results indicate that Chr5 had a high level of homogeneity, with the same genes being discovered across all breeds. In contrast, Chr1 displays some genetic variances between breeds. Genes identified on Chr5 included SLC39A1, IL23A, CAST, IL5, IL13, and IL4 which are responsible for immune response while genes identified on Chr1 include SOD1, SLAMF9, RTP4, CLDN1, and PRKAA2. ROH segment profile and effective population sizes patterns suggests that the genetic uniformity of studied breeds is the outcome of events that transpired between 250 and 300 generations ago. This research not only contributes to the understanding of ROH distribution across breeds but helps design and implement native sheep breeding and conservation strategies in Morocco. Future research, incorporating a broader sample size and utilizing the pangenome for reference, is recommended to further elucidate these breeds' genomic landscapes and adaptive mechanisms.

Fault in Our Genes: A Case of Pulmonary Thromboembolism in Young.

Methylenetetrahydrofolate reductase (MTHFR) enzyme is one of the key enzymes involved in the metabolism of folate. Mutations in this enzyme can lead to a procoagulant state. We present a case of a 20-year-old male with no known comorbidities, who presented with fever and hemoptysis and was diagnosed as a case of pulmonary embolism. He was found to have a homozygous mutation in the MTHFR gene that was responsible for his disease state. He was started on unfractionated heparin infusion and underwent catheter-directed thrombolysis. He showed marked improvement in his condition and was discharged on oral anticoagulants with an advice to follow-up.

RésuméL'enzyme méthylènetétrahydrofolate réductase (MTHFR) est l'une des enzymes clés impliquées dans le métabolisme du folate. Les mutations de cette enzyme peuvent conduire à un état procoagulant. Nous présentons le cas d'un homme de 20 ans sans comorbidités connues, qui s'est présenté avec de la fièvre et une hémoptysie et a été diagnostiqué comme un cas d'embolie pulmonaire. Il s'est avéré qu'il présentait une mutation homozygote du gène MTHFR responsable de son état pathologique. Il a commencé une perfusion d'héparine non fractionnée et a subi une thrombolyse dirigée par cathéter. Il a montré une nette amélioration de son état et a été libéré sous anticoagulants oraux avec un conseil de suivi.

A novel homozygous missense TTC12 variant identified in an infertile Pakistani man with severe oligoasthenoteratozoospermia and primary ciliary dyskinesia.

TTC12 is a cytoplasmic and centromere-localized protein that plays a role in the proper assembly of dynein arm complexes in motile cilia in both respiratory cells and sperm flagella. This finding underscores its significance in cellular motility and function. However, the wide role of TTC12 in human spermatogenesis-associated primary ciliary dyskinesia (PCD) still needs to be elucidated. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify potentially pathogenic variants causing PCD and multiple morphological abnormalities of sperm flagella (MMAF) in an infertile Pakistani man. Diagnostic imaging techniques were used for PCD screening in the patient. Real-time polymerase chain reaction (RT‒PCR) was performed to detect the effect of mutations on the mRNA abundance of the affected genes. Papanicolaou staining and scanning electron microscopy (SEM) were carried out to examine sperm morphology. Transmission electron microscopy (TEM) was performed to examine the ultrastructure of the sperm flagella, and the results were confirmed by immunofluorescence staining. Using WES and Sanger sequencing, a novel homozygous missense variant (c.C1069T; p.Arg357Trp) in TTC12 was identified in a patient from a consanguineous family. A computed tomography scan of the paranasal sinuses confirmed the symptoms of the PCD. RT-PCR showed a decrease in TTC12 mRNA in the patient's sperm sample. Papanicolaou staining, SEM, and TEM analysis revealed a significant change in shape and a disorganized axonemal structure in the sperm flagella of the patient. Immunostaining assays revealed that TTC12 is distributed throughout the flagella and is predominantly concentrated in the midpiece in normal spermatozoa. In contrast, spermatozoa from patient deficient in TTC12 showed minimal staining intensity for TTC12 or DNAH17 (outer dynein arms components). This could lead to MMAF and result in male infertility. This novel TTC12 variant not only illuminates the underlying genetic causes of male infertility but also paves the way for potential treatments targeting these genetic factors. This study represents a significant advancement in understanding the genetic basis of PCD-related infertility.

Evaluation of genomic prediction considering non-additive genetic effects on fatty acid traits of Japanese Black cattle.

Genomic prediction was conducted using 2494 Japanese Black cattle from Hiroshima Prefecture and both single-nucleotide polymorphism information and phenotype data on monounsaturated fatty acid (MUFA) and oleic acid (C18:1) analyzed with gas chromatography. We compared the prediction accuracy for four models (A, additive genetic effects; AD, as for A with dominance genetic effects; ADR, as for AD with the runs of homozygosity (ROH) effects calculated by ROH-based relationship matrix; and ADF, as for AD with the ROH-based inbreeding coefficient of the linear regression). Bayesian methods were used to estimate variance components. The narrow-sense heritability estimates for MUFA and C18:1 were 0.52-0.53 and 0.57, respectively; the corresponding proportions of dominance genetic variance were 0.04-0.07 and 0.04-0.05, and the proportion of ROH variance was 0.02. The deviance information criterion values showed slight differences among the models, and the models provided similar prediction accuracy.

Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.

Genetic diversity and selection signatures in Hainan black goats revealed by whole-genome sequencing data.

Understanding the genetic characteristics of indigenous goat breeds is crucial for their conservation and breeding efforts. Hainan black goats, as a native breed of south China's tropical island province of Hainan, possess distinctive traits such as black hair, a moderate growth rate, good meat quality, and small body size. However, they exhibit exceptional resilience to rough feeding conditions, possess high-quality meat, and show remarkable resistance to stress and heat. In this study, we resequenced the whole genome of Hainan black goats to study the economic traits and genetic basis of these goats, we leveraged whole-genome sequencing data from 33 Hainan black goats to analyze single nucleotide polymorphism (SNP) density, Runs of homozygosity (ROH), Integrated Haplotype Score (iHS), effective population size (Ne), Nucleotide diversity Analysis (Pi) and selection characteristics. Our findings revealed that Hainan black goats harbor a substantial degree of genetic variation, with a total of 23 608 983 SNPs identified. Analysis of ROHs identified 53 710 segments, predominantly composed of short fragments, with inbreeding events mainly occurring in ancient ancestors, the estimates of inbreeding based on ROH in Hainan black goats typically exhibit moderate values ranging from 0.107 to 0.186. This is primarily attributed to significant declines in the effective population size over recent generations. Moreover, we identified 921 candidate genes within the intersection candidate region of ROH and iHS. Several of these genes are associated with crucial traits such as immunity (PTPRC, HYAL1, HYAL2, HYAL3, CENPE and PKN1), heat tolerance (GNG2, MAPK8, CAPN2, SLC1A1 and LEPR), meat quality (ACOX1, SSTR1, CAMK2B, PPP2CA and PGM1), cashmere production (AKT4, CHRM2, OXTR, AKT3, HMCN1 and CDK19), and stress resistance (TLR2, IFI44, ENPP1, STK3 and NFATC1). The presence of these genes may be attributed to the genetic adaptation of Hainan black goats to local climate conditions. The insights gained from this study provide valuable references and a solid foundation for the preservation, breeding, and utilization of Hainan black goats and their valuable genetic resources.

[Experience with the use of risdiplam in a familial case of spinal muscular atrophy 5q in patients with a homozygous deletion of the SMN1 gene and the same copy number of the SMN2 gene]. / Opyt primeneniya risdiplama pri semeinom sluchae spinal'noi myshechnoi atrofii 5q u patsientov s gomozigotnoi deletsiei gena SMN1 i odinakovym kolichestvom kopii gena SMN2.

Advances in the treatment of spinal muscular atrophy (SMA) have revolutionized the field. SMA is a rare autosomal recessive neurodegenerative motor neuron disease in which wide phenotypic variability has been described. The rate of increase in neurological deficit and the severity of the disease is mainly determined by the amount of functional SMN (Survival of Motor Neuron) protein. However, the clinical picture may differ significantly in patients carrying homozygous deletions of the SMN1 gene (Survival of Motor Neuron 1) and an identical number of copies of the SMN2 gene (Survival of Motor Neuron 2). A family clinical case of adult patients with spinal muscular atrophy 5q with a homozygous deletion of the SMN1 gene and the same number of copies of the SMN2 gene, having a different clinical picture of the disease, is presented, and the dynamics of the condition against the background of oral pathogenetic therapy is presented.

Homozygosity in any HLA locus is a risk factor for specific antibody production: the taboo concept 2.0.

Objective: In a cooperative study of the University Hospital Leipzig, University of Leipzig, and the Charité Berlin on kidney transplant patients, we analysed the occurrence of HLA-specific antibodies with respect to the HLA setup of the patients. We aimed at the definition of specific HLA antigens towards which the patients produced these antibodies. Methods: Patients were typed for the relevant HLA determinants using mainly the next-generation technology. Antibody screening was performed by the state-of-the-art multiplex-based technology using microspheres coupled with the respective HLA alleles of HLA class I and II determinants. Results: Patients homozygous for HLA-A*02, HLA-A*03, HLA-A*24, HLA-B*07, HLA-B*18, HLA-B*35, HLA-B*44, HLA-C*03, HLA-C*04, and HLA-C*07 in the class I group and HLA-DRB1*01, HLA-DRB1*03, HLA-DRB1*07, HLA-DRB1*15, HLA-DQA1*01, HLA-DQA1*05, HLA-DQB1*02, HLA-DQB1*03(7), HLA-DQB1*06, HLA-DPA1*01, and HLA-DPB1*04 in the class II group were found to have a significant higher antibody production compared to the heterozygous ones. In general, all HLA determinants are affected. Remarkably, HLA-A*24 homozygous patients can produce antibodies towards all HLA-A determinants, while HLA-B*18 homozygous ones make antibodies towards all HLA-B and selected HLA-A and C antigens, and are associated with an elevation of HLA-DRB1, parts of DQB1 and DPB1 alleles. Homozygosity for the HLA class II HLA-DRB1*01, and HLA-DRB1*15 seems to increase the risk for antibody responses against most of the HLA class I antigens (HLA-A, HLA-B, and HLA-C) in contrast to HLA-DQB1*03(7) where a lower risk towards few HLA-A and HLA-B alleles is found. The widely observed differential antibody response is therefore to be accounted to the patient's HLA type. Conclusion: Homozygous patients are at risk of producing HLA-specific antibodies hampering the outcome of transplantation. Including this information on the allocation procedure might reduce antibody-mediated immune reactivity and prevent graft loss in a patient at risk, increasing the life span of the transplanted organ.

Genetic analysis of 106 sporadic cases with hearing loss in the UAE population.

BACKGROUND: Hereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE. RESULTS: In this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants. CONCLUSIONS: Our findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition.

Post-meiotic mechanism of facultative parthenogenesis in gonochoristic whiptail lizard species.

Facultative parthenogenesis (FP) has historically been regarded as rare in vertebrates, but in recent years incidences have been reported in a growing list of fish, reptile, and bird species. Despite the increasing interest in the phenomenon, the underlying mechanism and evolutionary implications have remained unclear. A common finding across many incidences of FP is either a high degree of homozygosity at microsatellite loci or low levels of heterozygosity detected in next-generation sequencing data. This has led to the proposal that second polar body fusion following the meiotic divisions restores diploidy and thereby mimics fertilization. Here, we show that FP occurring in the gonochoristic Aspidoscelis species A. marmoratus and A. arizonae results in genome-wide homozygosity, an observation inconsistent with polar body fusion as the underlying mechanism of restoration. Instead, a high-quality reference genome for A. marmoratus and analysis of whole-genome sequencing from multiple FP and control animals reveals that a post-meiotic mechanism gives rise to homozygous animals from haploid, unfertilized oocytes. Contrary to the widely held belief that females need to be isolated from males to undergo FP, females housed with conspecific and heterospecific males produced unfertilized eggs that underwent spontaneous development. In addition, offspring arising from both fertilized eggs and parthenogenetic development were observed to arise from a single clutch. Strikingly, our data support a mechanism for facultative parthenogenesis that removes all heterozygosity in a single generation. Complete homozygosity exposes the genetic load and explains the high rate of congenital malformations and embryonic mortality associated with FP in many species. Conversely, for animals that develop normally, FP could potentially exert strong purifying selection as all lethal recessive alleles are purged in a single generation.

Genetic assessment and candidate genes identification for breed-specific characteristics of Qingyuan partridge chicken based on runs of homozygosity.

BACKGROUND: Several core breeding and supporting lines of the Qingyuan partridge chicken, a representative local chicken breed in China, have been developed over 20 years. Consequently, its economic traits related to growth and reproduction have been significantly improved by breeding selection and commercial utilization, but some characteristic traits, such as partridge feathers, high meat quality and sufficient flavor, have always been retained. However, effective methods for genetic assessment and functional gene exploration of similar trait groups are lacking. The presence of identical haplotype fragments transmitted from parent to offspring results in runs of homozygosity (ROH), which offer an efficient solution. In this study, genomes of 134 Qingyuan partridge chickens representing two breeding populations and one preserved population were re-sequenced to evaluate the genetic diversity and explore functional genes by analyzing the diversity, distribution, and frequency of ROH. RESULTS: The results showed a low level of genomic linkage and degree of inbreeding within both the bred and preserved populations, suggesting abundant genetic diversity and an adequate genetic potential of the Qingyuan partridge chicken. Throughout the long-term selection process, 21 genes, including GLI3, ANO5, BLVRA, EFNB2, SLC5A12, and SVIP, associated with breed-specific characteristics were accumulated within three ROH islands, whereas another 21 genes associated with growth traits including IRX1, IRX2, EGFR, TPK1, NOVA1, BDNF and so on were accumulated within five ROH islands. CONCLUSIONS: These findings provide new insights into the genetic assessment and identification of genes with breed-specific and selective characteristics, offering a solid genetic basis for breeding and protection of Qingyuan partridge chickens.