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Taiwanese Journal of Obstetrics &... Jun 2012To present second-trimester ultrasound and molecular diagnosis for osteogenesis imperfecta (OI) type I in a female fetus and incidental identification of a dominant...
OBJECTIVE
To present second-trimester ultrasound and molecular diagnosis for osteogenesis imperfecta (OI) type I in a female fetus and incidental identification of a dominant COL1A1 deletion mutation in her paucisymptomatic father.
CASE REPORT
A 30-year-old, primigravid woman was referred for genetic counseling in the second trimester because of bowing of the fetal lower limbs. She and her husband were non-consanguineous, and there was no family history of skeletal dysplasias. Prenatal ultrasound at 22 weeks of gestation revealed short and curved right femur and left tibia, and a short left fibula. The lengths of other long bones were normal. The husband was 158 cm tall, had blue sclerae, a history of habitual subluxation and dislocation of bilateral elbows and left knee, and an episode of left ulna fracture, and was not aware of his being affected with OI type I. The woman underwent amniocentesis. Cytogenetic analysis revealed a karyotype of 46,XX. Molecular analysis of the amniocytes revealed a heterozygous deletion mutation of c.1064_1068delCTGGT in exon 17 of the COL1A1 gene. By genetic testing the husband was found to carry the same mutation. Despite counseling of favorable outcome for OI type I with the parents, the woman elected to terminate the pregnancy. Postnatal skeletal X-ray findings were consistent with OI type I.
CONCLUSION
Prenatal ultrasound diagnosis of mild forms of OI should include molecular analysis of type I collagen genes in both fetus and parents. Molecular genetic analysis of the family may incidentally identify a collagen gene mutation in the paucisymptomatic affected parent.
Topics: Adult; Amniocentesis; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Heterozygote; Humans; Karyotype; Male; Osteogenesis Imperfecta; Pedigree; Pregnancy; Pregnancy Trimester, Second; Radiography; Sequence Deletion; Ultrasonography, Prenatal
PubMed: 22795108
DOI: 10.1016/j.tjog.2012.04.020 -
Diagnostic Pathology May 2013Congenital generalized lipodystrophy (CGL) also known as Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a genetically heterogeneous disorder characterized by loss...
BACKGROUND
Congenital generalized lipodystrophy (CGL) also known as Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a genetically heterogeneous disorder characterized by loss of adipose tissues, Acanthosis nigricans, diabetes mellitus, muscular hypertrophy, hepatomegaly and hypertriglyceridemia. There are four subclinical phenotypes of CGL (CGL1-4) and mutations in four genes AGPAT2, BSCL2, CAV1 and PTRF have been assigned to each type.
METHODS
The study included clinical and molecular investigations of CGL disease in a consanguineous Pakistani family. For mutation screening all the coding exons including splice junctions of AGPAT2, BSCL2, CAV1 and PTRF genes were PCR amplified and sequenced directly using an automated DNA sequencer ABI3730.
RESULTS
Sequence analysis revealed a single base pair deletion mutation (c.636delC; p.Tyr213ThrfsX20) in exon 5 of BSCL2 gene causing a frame shift and premature termination codon.
CONCLUSION
Mutation identified here in BSCL2 gene causing congenital generalized lipodystrophy is the first report in Pakistani population. The patients exhibited characteristic features of generalized lipodystrophy, Acanthosis nigricans, diabetes mellitus and hypertrophic cardiomyopathy.
VIRTUAL SLIDES
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1913913076864247.
Topics: Acanthosis Nigricans; Base Sequence; Codon, Nonsense; Exons; Female; GTP-Binding Protein gamma Subunits; Genetic Testing; Humans; Lipodystrophy, Congenital Generalized; Male; Pakistan; Pedigree; Phenotype; Sequence Deletion
PubMed: 23659685
DOI: 10.1186/1746-1596-8-78 -
Cancer Research Apr 2008Genomic analyses of late-stage human cancers have uncovered deletions encompassing 1p36, thereby providing an extensive body of literature supporting the idea that a... (Review)
Review
Genomic analyses of late-stage human cancers have uncovered deletions encompassing 1p36, thereby providing an extensive body of literature supporting the idea that a potent tumor suppressor resides in this interval. Although several genes have been proposed as 1p36 candidate tumor suppressors, convincing evidence that their encoded products protect from cancer has been scanty. A recent functional study identified chromodomain helicase DNA-binding protein 5 (CHD5) as a novel tumor suppressor mapping to 1p36. Here, we discuss evidence supporting the tumor-suppressive role of CHD5. Together, these findings suggest that strategies designed to enhance CHD5 activity could provide novel approaches for treating a broad range of human malignancies.
Topics: Chromatin; Chromosome Mapping; Chromosomes, Human, Pair 1; DNA Helicases; Gene Deletion; Genes, Tumor Suppressor; Humans; Mutation; Neoplasms; Nerve Tissue Proteins; Sequence Deletion
PubMed: 18413720
DOI: 10.1158/0008-5472.CAN-07-2095 -
PloS One 2022Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a...
Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir's effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.
Topics: Animals; Child, Preschool; Humans; Male; Rats; Adenosine Monophosphate; Alanine; COVID-19; DNA Copy Number Variations; DNA, Mitochondrial; DNA-Directed RNA Polymerases; Mammals; Mitochondria; Nucleosides; RNA, Viral; SARS-CoV-2; Sequence Deletion
PubMed: 36288327
DOI: 10.1371/journal.pone.0271850 -
BMC Medical Genetics Jul 2018Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including...
BACKGROUND
Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion.
METHODS
Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene.
RESULTS
The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele.
CONCLUSION
This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.
Topics: Exons; Female; Heterozygote; Homozygote; Humans; India; Infant; Male; Mutation, Missense; Sequence Deletion; Tay-Sachs Disease; beta-Hexosaminidase alpha Chain
PubMed: 29973161
DOI: 10.1186/s12881-018-0632-7 -
Journal of Cancer Research and... 2015BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine... (Meta-Analysis)
Meta-Analysis
AIM
BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC). However, accumulating evidences concerning the association between BIM deletion polymorphism and efficacy of EGFR-TKI and survival in EGFR-mutation-driven NSCLC patient reported contradictory results.
MATERIALS AND METHODS
A meta-analysis was conducted by combing six original eligible studies including 871 NSCLC patients.
RESULTS
Our study showed that BIM deletion polymorphism was significantly associated with poor response to EGFR-TKI therapy in mutant EGFRNSCLC patients (P(h) = 0.309, P(z) = 0.001, OR = 0.39, 95% confidence interval (CI) = 0.23-0.67). Disease control rate (DCR) in mutant EGFRNSCLC patient with treatment of EGFR-TKI was significantly decreased in patients with BIM deletion polymorphism comparing to patients harbored BIM wild variant (P(h) = 0.583, P(Z) = 0.007, OR = 0.46, 95%CI = 0.25-0.85). EGFR mutation-derived NSCLC patient carrying BIM deletion polymorphism had a shorter progression-free survival (PFS; P(h) < 0.001, P(z) < 0.001, hazard ratio (HR) = 1.37, 95%CI = 1.09-1.71) and overall survival (OS; P(h) = 0.90, P(z) = 0.003, HR = 1.25, 95%CI = 1.08-1.45), than those harbored BIM wild variant.
CONCLUSION
These results suggested that BIM deletion polymorphism might be a cause that contributes to primary EGFR-TKI resistance, and it could be used as a genetic predictor for EGFR-TKI outcome and an independent prognostic factor of EGFR mutation-driven NSCLC patient.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; ErbB Receptors; Humans; Lung Neoplasms; Polymorphism, Genetic; Protein Kinase Inhibitors; Sequence Deletion
PubMed: 26148607
DOI: 10.4103/2152-7806.157308 -
Genome Research Apr 2018Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods....
Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABA's performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs and substantially improves detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (<1000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types and found that short templated-sequence insertions occur in ∼4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized (50-300 bp) SVs.
Topics: Databases, Genetic; Genome, Human; Genomic Structural Variation; Genomics; High-Throughput Nucleotide Sequencing; Humans; INDEL Mutation; Sequence Analysis, DNA; Sequence Deletion; Software; Virus Integration
PubMed: 29535149
DOI: 10.1101/gr.221028.117 -
Medicine Feb 2019Parkinson disease (PD) is a complex neurodegenerative movement disorder characterized by resting tremor, muscular rigidity, bradykinesia, and so on. Genetics has been...
RATIONALE
Parkinson disease (PD) is a complex neurodegenerative movement disorder characterized by resting tremor, muscular rigidity, bradykinesia, and so on. Genetics has been regarded as an important role in the development of PD. PARK2, an autosomal recessive gene, is the most common one referring to early-onset Parkinson disease (EOPD). Strangely, only a single heterozygous mutation in PARK2 was found in a small minority of patients with PD, which has been reported quite rarely and is difficult to explain.
PATIENT CONCERNS
We described a case of 36-year-old male patient, complaining of progressive tremor for 10 years. He 1st presented uncontrolled resting tremor of his left arm. Besides, he also had trouble in completing fine motor tasks such as writing and buttoning. Six years later, tremor of the ipsilateral leg gradually occurred. On neurologic examinations, pronounced parkinsonian symptoms were noted, including resting tremor, body bradykinesia, and hypomimia. The positron emission tomography-computed tomography showed the distribution of dopamine transporter in both putamens decreased obviously. No family history was indentified. He came to hospital because his disease aggravated in the past 4 months.
DIAGNOSIS
This patient was diagnosed with PD according to the movement disorder society clinical diagnostic criteria for PD.
INTERVENTIONS AND OUTCOMES
With regard to the sequencing of this patient, a heterozygous point mutation of G403C in PARK2 was detected, which was inherited from his unaffected mother, leading to an amino acid alternation of glycine to arginine. Furthermore, deletion mutation of exon 6 in PARK2 was also found in this patient, which was inherited from his normal father. He accepted madopar and benzhexol and showed stable efficacy. To our knowledge, it is the 1st case report to explain the synergistic action of both heterozygous pathogenic point mutation in PARK2 and deletion mutation of exon 6 leading to EOPD.
LESSONS
Compound heterozygous mutations in PARK2 with point mutation of G403C and deletion mutation of exon 6 might contribute to the development of EOPD.
Topics: Adult; Age of Onset; Humans; Male; Parkinson Disease; Polymorphism, Single Nucleotide; Sequence Deletion; Ubiquitin-Protein Ligases
PubMed: 30702579
DOI: 10.1097/MD.0000000000014228 -
Nature Communications Oct 2019The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair...
The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.
Topics: Base Sequence; CRISPR-Cas Systems; DNA End-Joining Repair; Gain of Function Mutation; Gene Editing; Humans; Induced Pluripotent Stem Cells; Loss of Function Mutation; Sequence Deletion
PubMed: 31649251
DOI: 10.1038/s41467-019-12829-8 -
G3 (Bethesda, Md.) Jan 2019In at least some unicellular organisms, mutation rates are temporarily raised upon exposure to environmental stress, potentially contributing to the evolutionary...
In at least some unicellular organisms, mutation rates are temporarily raised upon exposure to environmental stress, potentially contributing to the evolutionary response to stress. Whether this is true for multicellular organisms, however, has received little attention. This study investigated the effects of chronic mild stress, in the form of low-level copper and nickel exposure, on mutational processes in using a combination of mutation accumulation, whole genome sequencing and life-history assays. After over 100 generations of mutation accumulation, we found no effects of metal exposure on the rates of single nucleotide mutations and of loss of heterozygosity events, the two mutation classes that occurred in sufficient numbers to allow statistical analysis. Similarly, rates of decline in fitness, as measured by intrinsic rate of population increase and of body size at first reproduction, were negligibly affected by metal exposure. We can reject the possibility that were insufficiently stressed to invoke genetic responses as we have previously shown rates of large-scale deletions and duplications are elevated under metal exposure in this experiment. Overall, the mutation accumulation lines did not significantly depart from initial values for phenotypic traits measured, indicating the lineage used was broadly mutationally robust. Taken together, these results indicate that the mutagenic effects of chronic low-level exposure to these metals are restricted to certain mutation classes and that fitness consequences are likely minor and therefore unlikely to be relevant in determining the evolutionary responses of populations exposed to these stressors.
Topics: Animals; Copper; Daphnia; Genetic Fitness; Genome; Mutation; Mutation Accumulation; Mutation Rate; Nickel; Reproduction; Sequence Deletion
PubMed: 30389796
DOI: 10.1534/g3.118.200797