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Homozygote - Top 30 Publications

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically.

Rapid RHD Zygosity Determination Using Digital PCR.

Paternal zygosity testing is used for determining homo- or hemizygosity of RHD in pregnancies that are at a risk of hemolytic disease of the fetus and newborn. At present, this is achieved by using real-time PCR or the Rhesus box PCR, which can be difficult to interpret and unreliable, particularly for black African populations.

A case report of pedigree of a homozygous mutation of the steroidogenic acute regulatory protein causing lipoid congenital adrenal hyperplasia.

Lipoid congenital adrenal hyperplasia (LCAH) is extremely rare, but is the most fatal form of congenital adrenal hyperplasia resulting from mutations in the steroidogenic acute regulatory protein (STAR) gene. LCAH arises from severe defects in the conversion of cholesterol to pregnenolone, the precursor of all steroids.

Survival rates of homozygotic Tp53 knockout rats as a tool for preclinical assessment of cancer prevention and treatment.

The gene that encodes tumor protein p53, Tp53, is mutated or silenced in most human cancers and is recognized as one of the most important cancer drivers. Homozygotic Tp53 knockout mice, which develop lethal cancers early in their lives, are already used in cancer prevention studies, and now Tp53 knockout rats have also been generated. This study assessed feasibility of using homozygous Tp53 knockout rats to evaluate the possible outcome of cancer chemoprevention.

The distribution of runs of homozygosity and selection signatures in six commercial meat sheep breeds.

Domestication and the subsequent selection of animals for either economic or morphological features can leave a variety of imprints on the genome of a population. Genomic regions subjected to high selective pressures often show reduced genetic diversity and frequent runs of homozygosity (ROH). Therefore, the objective of the present study was to use 42,182 autosomal SNPs to identify genomic regions in 3,191 sheep from six commercial breeds subjected to selection pressure and to quantify the genetic diversity within each breed using ROH. In addition, the historical effective population size of each breed was also estimated and, in conjunction with ROH, was used to elucidate the demographic history of the six breeds. ROH were common in the autosomes of animals in the present study, but the observed breed differences in patterns of ROH length and burden suggested differences in breed effective population size and recent management. ROH provided a sufficient predictor of the pedigree inbreeding coefficient, with an estimated correlation between both measures of 0.62. Genomic regions under putative selection were identified using two complementary algorithms; the fixation index and hapFLK. The identified regions under putative selection included candidate genes associated with skin pigmentation, body size and muscle formation; such characteristics are often sought after in modern-day breeding programs. These regions of selection frequently overlapped with high ROH regions both within and across breeds. Multiple yet uncharacterised genes also resided within putative regions of selection. This further substantiates the need for a more comprehensive annotation of the sheep genome as these uncharacterised genes may contribute to traits of interest in the animal sciences. Despite this, the regions identified as under putative selection in the current study provide an insight into the mechanisms leading to breed differentiation and genetic variation in meat production.

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity.

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.

T/T homozygosity of the tenascin-C gene polymorphism rs2104772 negatively influences exercise-induced angiogenesis.

Mechanical stress, including blood pressure related factors, up-regulate expression of the pro-angiogenic extracellular matrix protein tenascin-C in skeletal muscle. We hypothesized that increased capillarization of skeletal muscle with the repeated augmentation in perfusion during endurance training is associated with blood vessel-related expression of tenascin-C and would be affected by the single-nucleotide polymorphism (SNP) rs2104772, which characterizes the non-synonymous exchange of thymidine (T)-to-adenosine (A) in the amino acid codon 1677 of tenascin-C.

A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome.

PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks.

GNE myopathy in a Chinese male with a novel homozygous mutation.

GNE myopathy is a rare autosomal recessive inheritance disease due to the mutation of GNE gene. To date, 107 mutations have been reported in different populations worldwide in GNE gene(HGMD Professional 2016.2). Here we report a patient of novel homozygous GNE gene mutation from China.

Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation.

We study the phenotype and genotype of a novel gene mutation of factor II (FII) that leads to dysprothrombinemia, and do the meta-analysis to illuminate its molecular pathogenesis. It will further contribute to our comprehension of the pathogenesis of this type of disease.

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.

TOMM40'523 variant and cognitive decline in older persons with APOE ε3/3 genotype.

To interrogate a poly-T variant (rs10524523, '523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).

Identification of a novel FUT1 allele with two mutations in a Chinese para-Bombay individual.

The para-Bombay phenotype often results from a silenced β-D-galactoside 2-α-fucosyltransferase 1 (FUT1) gene (h/h) but an active FUT2 (Se/Se or Se/se) gene. We identified a para-Bombay phenotype with two novel mutations in the FUT1 gene and homozygous mutated FUT2 (se(357, 385) /se(357, 385) ) genes.

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.

SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies.

Runs of homozygosity: current knowledge and applications in livestock.

This review presents a broader approach to the implementation and study of runs of homozygosity (ROH) in animal populations, focusing on identifying and characterizing ROH and their practical implications. ROH are continuous homozygous segments that are common in individuals and populations. The ability of these homozygous segments to give insight into a population's genetic events makes them a useful tool that can provide information about the demographic evolution of a population over time. Furthermore, ROH provide useful information about the genetic relatedness among individuals, helping to minimize the inbreeding rate and also helping to expose deleterious variants in the genome. The frequency, size and distribution of ROH in the genome are influenced by factors such as natural and artificial selection, recombination, linkage disequilibrium, population structure, mutation rate and inbreeding level. Calculating the inbreeding coefficient from molecular information from ROH (FROH ) is more accurate for estimating autozygosity and for detecting both past and more recent inbreeding effects than are estimates from pedigree data (FPED ). The better results of FROH suggest that FROH can be used to infer information about the history and inbreeding levels of a population in the absence of genealogical information. The selection of superior animals has produced large phenotypic changes and has reshaped the ROH patterns in various regions of the genome. Additionally, selection increases homozygosity around the target locus, and deleterious variants are seen to occur more frequently in ROH regions. Studies involving ROH are increasingly common and provide valuable information about how the genome's architecture can disclose a population's genetic background. By revealing the molecular changes in populations over time, genome-wide information is crucial to understanding antecedent genome architecture and, therefore, to maintaining diversity and fitness in endangered livestock breeds.

Rapid Molecular Genetic Diagnosis with Next-Generation Sequencing in 46,XY Disorders of Sex Development Cases: Efficiency and Cost Assessment.

The aim of this study was to use targeted next-generation sequencing (TNGS) including all known genes associated with 46,XY disorders of sex development (DSD) for a fast molecular genetic diagnosis.

Characterization and management of long runs of homozygosity in parental nucleus lines and their associated crossbred progeny.

In nucleus populations, regions of the genome that have a high frequency of runs of homozygosity (ROH) occur and are associated with a reduction in genetic diversity, as well as adverse effects on fitness. It is currently unclear whether, and to what extent, ROH stretches persist in the crossbred genome and how genomic management in the nucleus population might impact low diversity regions and its implications on the crossbred genome.

The complexities of homozygous familial hypercholesterolemia management.

LGMD2D syndrome: the importance of clinical and molecular genetics in patient and family management. Case Report.

We report the case of a seven-year-old female from a consanguineous Saudi family with autosomal recessive limb girdle muscular dystrophy type 2D (LGMD2D) most likely caused by a rare SGCA mutation. Histopathological and molecular investigations resulted in the discovery of a homozygous mutation (c.226 C>T (p.L76 F)) in exon 3 of SGCA in the patient. The parents and one sibling were heterozygous carriers, but the mutation was not otherwise detected in 80 ethnic controls from the same geographic area. In silico analysis revealed that the mutation resulted in a functional leucine to phenylalanine alteration that was deleterious to the protein structure. This is only the second reported case of the p.L76F mutation in LGMD, and highlights that molecular genetics analysis is essential to deliver the most appropriate management to the patient and offer the family genetic counseling.

A Jordanian family with three sisters apparently homozygous for M(k) and evidence for clinical significance of antibodies produced by M(k) M(k) individuals.

The rare M(k) M(k) phenotype is the result of a deletion of the coding regions of both GYPA and GYPB. Red blood cells (RBCs) of individuals homozygous for the rare M(k) gene lack all MNS blood group antigens and have no glycophorin A or glycophorin B. This phenotype is extremely rare and only four families have been reported.

HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype-stratified cohort study of hemochromatosis in Australian women.

Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups.

Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes.

Genetic polymorphisms in patients with acute lymphoblastic leukemia (ALL) may influence the toxicity of chemotherapeutic agents. Due to the importance of the transport P-glycoprotein and methylenetetrahydrofolate reductase in the metabolism of chemotherapeutic agents, we analyzed the MDR1 rs1045642 and MTHFR rs1801133 polymorphisms and their associations with clinical outcomes in Mexican childhood ALL patients.

A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly.

Osteogenesis imperfecta (OI) is a genetic disorder characterised by low bone mineral density resulting in fractures. 85-90% of patients with OI carry a variant in the type 1 collagen genes, COL1A1 and COL1A2, which follows an autosomal dominant pattern of inheritance. However, within the last two decades, there have been growing number of variants identified in genes that follow an autosomal recessive pattern of inheritance. Our proband is a child born in Mexico with multiple fractures of ribs, minimal calvarial mineralisation, platyspondyly, marked compression and deformed long bones. He also presented with significant hydranencephaly, requiring ventilatory support from birth, and died at 8days of age. A homozygous c.338_357delins22 variant in exon 2 of SERPINH1 was identified. This gene encodes heat shock protein 47, a collagen-specific chaperone which binds to the procollagen triple helix and is responsible for collagen stabilisation in the endoplasmic reticulum. There is minimal literature on the mechanism of action for variants in SERPINH1 resulting in osteogenesis imperfecta. Here we discuss this rare, previously unreported variant, and expand on the phenotypic presentation of this novel variant resulting in a severe, lethal phenotype of OI in association with hydranencephaly.

Investigation of association between IL-8 serum levels and IL8 polymorphisms in Chinese patients with sepsis.

To assess the clinical relevance of IL8 gene polymorphisms in patients with sepsis and its association with systemic IL-8 levels.

A novel homozygous HOXB1 mutation in a Turkish family with hereditary congenital facial paresis.

Hereditary congenital facial paresis (HCFP) is characterized by isolated dysfunction of the facial nerve (CN VII) due to congenital cranial dysinnervation disorders. HCFP has genetic heterogeneity and HOXB1 is the first identified gene. We report the clinical, radiologic and molecular investigations of three patients admitted for HCFP in a large consanguineous Turkish family. High-throughput sequencing and Sanger sequencing of all patients revealed a novel homozygous mutation p.Arg230Trp (c.688C>T) within the HOXB1 gene. The report of the mutation brings the total number of HOXB1 mutations identified in HCFP to four. The results of this study emphasize that in individuals with congenital facial palsy accompanied by hearing loss and dysmorphic facial features, HOXB1 mutation causing HCFP should be kept in mind.

A case of sudden unexpected infant death involving a homozygotic twin with the thermolabile CPT2 variant, accompanied by rotavirus infection and treatment with an antibiotic containing pivalic acid.

We investigated a case of sudden unexpected death involving a 22-month-old male homozygotic twin infant. After both of the twins had suffered from gastroenteritis, one was found dead in his bed, but his brother survived and has since been healthy. Notably, only the deceased had been treated with an antibiotic containing pivalic acid, which may sometimes cause hypocarnitinemia. Postmortem computed tomography and medicolegal autopsy demonstrated severe liver steatosis, and subsequent genetic analysis revealed that the twin had the thermolabile variant of carnitine palmitoyl transferase 2 (CPT2). On the basis of these facts, we concluded that the cause of death had been fatty acid oxidation deficiency accelerated by an antibiotic containing pivalic acid and virus infection in this infant harboring the thermolabile genetic variant of CPT2. Although each factor alone was not fatal, their combination appeared to have resulted in sudden unexpected infant death.

Increased homozygosity in the first Hispanic patient with plantar lipomatosis, unusual facies, and developmental delay (Pierpont syndrome): a case report.

Pierpont syndrome was first described in 1998 with key characteristics including developmental delay, dysmorphic facial features, fat pads on hands and feet, and feeding difficulties. To date the mechanism of inheritance is unknown. Nine out of ten previously described patients with Pierpont syndrome were boys. This is the first report of a case of a non-white patient with Pierpont syndrome and she is the second female patient to be described as having Pierpont syndrome.

Variant detection and runs of homozygosity in next generation sequencing data elucidate the genetic background of Lundehund syndrome.

The Lundehund is a highly specialized breed characterized by a unique flexibility of the joints and polydactyly in all four limbs. The extremely small population size and high inbreeding has promoted a high frequency of diseased dogs affected by the Lundehund syndrome (LS), a severe gastro-enteropathic disease.

Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic.

Homozygous and heterozygous point mutations in succinate dehydrogenase subunits b, c and d of Rhizoctonia cerealis conferring resistance to thifluzamide.

Thifluzamide, a succinate dehydrogenase inhibitor (SDHI) fungicide, is a promising fungicide for controlling wheat sharp eyespot (WSE). WSE is caused by Rhizoctonia cerealis. Information on the resistance mechanism of this pathogen to thifluzamide remains unavailable.