The latest medical research on Clinical Genetics

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about clinical genetics gathered by our medical AI research bot.

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Evaluation of licofelone as an adjunct anti-inflammatory therapy to biologic scaffolds in the treatment of volumetric muscle loss.

Cell and Tissue Research

Biologic scaffolds (BS) are the most widely studied therapeutics for the treatment of volumetric muscle loss (VML) owing to their purported effects...

Comparative morphological and molecular studies on the oxygen-chemoreceptive cells in the carotid body and fish gills.

Cell and Tissue Research

Oxygen-chemoreceptive cells play critical roles for the respiration control. This review summarizes the chemoreceptive cells in the carotid body an...

Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans.

Genet Med

Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated.

We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study.

We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype.

These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.

Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield.

Genet Med

Expansions of a subset of short tandem repeats (STRs) have been implicated in approximately 30 different human genetic disorders. Despite extensive application of exome sequencing (ES) in routine diagnostic genetic testing, STRs are not routinely identified from these data.

We assessed diagnostic utility of STR analysis in exome sequencing by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes.

We identified 38 movement disorder patients with a possible aberrant STR length. Validation by polymerase chain reaction (PCR) and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 13 (34%). For seven of these patients the genotype was compatible with the phenotypic description, resulting in a molecular diagnosis. We subsequently tested the remainder of our diagnostic ES cohort, including over 30 clinically and genetically heterogeneous disorders. Optimized manual curation yielded 167 samples with a likely aberrant STR length. Validations confirmed 93/167 (56%) aberrant expansion alleles, of which 48 were in the pathogenic range and 45 in the premutation range.

Our work provides guidance for the implementation of STR analysis in clinical ES. Our results show that systematic STR evaluation may increase diagnostic ES yield by 0.2%, and recommend making STR evaluation a routine part of ES interpretation in genetic testing laboratories.

PP7080 expedites the proliferation and migration of lung adenocarcinoma cells via sponging miR-670-3p and regulating UHRF1BP1.

J Gene Med

An increasing body of evidence has revealed that lncRNAs play a significant part in a variety of human cancers; lung adenocarcinoma (LUAD) is included.

The expression of PP7080, miR-670-3p and UHRF1BP1 in LUAD cells and tissues was detected by using RT-qPCR. The role of PP7080 in LUAD cells was validated by CCK-8, flow cytometry, colony formation, transwell and wound healing assays. Then the binding capacity between PP7080/UHRF1BP1 and miR-670-3p was confirmed by luciferase reporter assays. Moreover, the interactional mechanism among PP7080, miR-670-3p and UHRF1BP1 was determined by means of RIP and western blot assays.

The expression level of PP7080 is up-regulated in LUAD cells and tissues by comparing with their matched controls. Down-regulation of PP7080 restrained the proliferative and migratory abilities of LUAD cells, but induced cell apoptosis; PP7080 up-regulation led to the opposite results. Moreover, the binding ability between miR-670-3p and PP7080/UHRF1BP1 in LUAD cells was confirmed. Rescue assay identified that PP7080 contributes to LUAD development via modulating miR-670-3p/UHRF1BP1 signaling pathway.

PP7080 expedites proliferation and migration of LUAD cell via sponging miR-670-3p and modulating UHRF1BP1.

Gene expression of bovine endometrial epithelial cells cultured in matrigel.

Cell and Tissue Research

Glandular epithelial cells (GE) in the endometrium are thought to support the elongation and survival of ruminant embryos by secreting histotrophs....

Cyclically stretched ACL fibroblasts emigrating from spheroids adapt their cytoskeleton and ligament-related expression profile.

Cell and Tissue Research

Mechanical stress of ligaments varies; hence, ligament fibroblasts must adapt their expression profile to novel mechanomilieus to ensure tissue res...

Description of the larval and adult hindgut tract of the common spider crab Maja brachydactyla Balss, 1922 (Brachyura, Decapoda, Malacostraca).

Cell and Tissue Research

Arthropods are the most diversified animals on Earth. The morphology of the digestive system has been widely studied in insects; however, crustacea...

Complete remission following icotinib administration in advanced ectopic thymic carcinoma patient harbouring EGFR exon 19 deletion.

J Gene Med

Ectopic thymic carcinoma (TC) is an extremely rare disease with a poor prognosis. Whereas the main treatment for early TC is surgery, effective treatment for advanced TC is lacking.

We present here the case of a 61-year-old man with advanced posterior mediastinum thymic squamous cell carcinoma. Amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) analysis were used to investigate the molecular and mutational characteristics of this tumour.

After chemotherapy and radiotherapy, the tumour showed disease progression. Immunohistochemistry revealed that the tumour was positive for CD117 (specific for primary TC), CK19, CD56, and Ki67. ARMS-PCR analysis revealed an EGFR exon 19 deletion in the patient. The patient subsequently received icotinib treatment and achieved complete remission for 3 years.

This case report suggests that tyrosine kinase inhibitors are a potential treatment strategy for patients with TC having EGFR alterations.

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.

Genet Med

We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).

Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.

Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.

Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

Genet Med

Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI.

From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies.

MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI.

MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.

Development of novel quality control material based on CRISPR/Cas9 editing and xenografts for MLH1 protein deficiency testing.

Clinical Laboratory

Mismatch repair deficiency (dMMR) status induced by MLH1 protein deficiency plays a pivotal role in therapeutic decision-making for cancer patients. Appropriate quality control (QC) materials are necessary for monitoring the accuracy of MLH1 protein deficiency assays used in clinical laboratories.

CRISPR/Cas9 technology was used to edit the MLH1 gene of GM12878Cas9 cells to establish MLH1 protein-deficient cell lines. The positive cell lines were screened and validated by Sanger sequencing, Western blot (WB), and next-generation sequencing (NGS) and were then used to prepare formalin-fixed, paraffin-embedded (FFPE) samples through xenografting. These FFPE samples were tested by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) for suitability as novel QC materials for MLH1 protein deficiency testing.

We successfully cultured 358 monoclonal cells, with a survival rate of 37.3% (358/960) of the sorted monoclonal cells. Through Sanger sequencing, cell lines with MLH1 gene mutation were identified. Subsequently, two cell lines with MLH1 protein deficiency were identified by WB and named as GM12878Cas9_6 and GM12878Cas9_10. The NGS results further confirmed that the MLH1 gene mutation in these two cell lines would cause the formation of stop codons and terminate the expression of the MLH1 protein. The H&E staining and IHC results also verified the deficiency of the MLH1 protein, and FFPE samples from xenografts proved their similarity and consistency with clinical samples.

We successfully established MLH1 protein-deficient cell lines. Followed by xenografting, we developed novel FFPE QC materials with homogenous, sustainable, and typical histological structures advantages that are suitable for the standardization of clinical IHC methods.