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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Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients.


Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal en...

Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort.

Genet Med

We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors.

Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability.

In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653.

The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.

Genet Med

Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing.

Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing.

Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2.

Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.

LINC00319 Promotes Osteosarcoma Progression by Regulating the miR-455-3p/NFIB Axis.

J Gene Med

Numerous studies have shown that the aberrant expression of lncRNAs is associated with the development and metastasis of osteosarcoma (OS). However, the role and function of LINC00319 in regulating OS progression is unknown. The current study aimed to reveal the function and related mechanism of LINC00319 in OS.

The expression of LINC00319, miR-455-3p and nuclear factor IB (NFIB) in OS cells and tissues was determined using real-time PCR. The sub-localization of LINC00319 was predicted by the LncATLAS database, and RNA fluorescence in situ hybridization (FISH) was further performed to detect the subcellular localization of LINC00319. LINC00319, miR-455-3p and NFIB target sites were predicted by the StarBase database and validated by using a dual luciferase reporter gene assay. We subsequently performed LINC00319 gain- and loss-of-function studies to define the role of LINC00319 in OS cell migration.

PCR results showed that lncRNA LINC00319 exhibited high expression in tumor cells and tissue. Moreover, LINC00319 was positioned in the cytoplasm, which was identified by FISH. Knockdown of lncRNA LINC00319/NFIB or overexpression of miR-455-3p blocked the migration of OS cells. In addition, the inhibitory effect of migration with the knockdown of lncRNA LINC00319 was partially blocked by administration of miR-455-3p inhibitor.

slncRNA LINC00319 may promote OS progression by regulating the miR-455-3p/NFIB axis, which probably serves as an innovative potential indicator of prognosis and target of therapy for OS.

Teaching clinicians practical genomic medicine: 7 years' experience in a tertiary care center.

Genet Med

Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model.

We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability.

During 2012-2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p < 0.001). Residents initially had higher scores than specialists (pre: 66.3 ± 17.3 vs. 58.7 ± 16.6, respectively, p = 0.002); both significantly improved, with specialists "catching up" (post: 79.1 ± 17.2 vs. 75.7 ± 15.9, nonsignificant (NS)); there was a similar trend between fellows and subspecialists (pre: 70 ± 18 vs. 59.4 ± 16.4, respectively, p = 0.007; post: 78.6 ± 16.4 vs. 73.2 ± 17.7, respectively, NS). Younger specialists (≤10 years residency) had significantly higher pre- and post scores. Absolute improvement in scores did not depend on medical specialties.

Our program is effective in improving genomics literacy for clinicians, irrespective of career length or expertise, and could be a model for improving skills in practical genomics for all medical professionals.

Disabled-2: a positive regulator of the early differentiation of myoblasts.

Cell and Tissue Research

Dab2 is an adaptor protein and a tumor suppressor. Our previous study has found that Dab2 was expressed in early differentiating skeletal muscles i...

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

Genet Med

To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.

We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.

One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.

Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines.

Genet Med

Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk.

For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data.

Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve.

Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.

Clinical outcomes of a genomic screening program for actionable genetic conditions.

Genet Med

Three genetic conditions-hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia-have tier 1 evidence for interventions that reduce morbidity and mortality, prompting proposals to screen unselected populations for these conditions. We examined the impact of genomic screening on risk management and early detection in an unselected population.

Observational study of electronic health records (EHR) among individuals in whom a pathogenic/likely pathogenic variant in a tier 1 gene was discovered through Geisinger's MyCode project. EHR of all eligible participants was evaluated for a prior genetic diagnosis and, among participants without such a diagnosis, relevant personal/family history, postdisclosure clinical diagnoses, and postdisclosure risk management.

Eighty-seven percent of participants (305/351) did not have a prior genetic diagnosis of their tier 1 result. Of these, 65% had EHR evidence of relevant personal and/or family history of disease. Of 255 individuals eligible to have risk management, 70% (n = 179) had a recommended risk management procedure after results disclosure. Thirteen percent of participants (41/305) received a relevant clinical diagnosis after results disclosure.

Genomic screening programs can identify previously unrecognized individuals at increased risk of cancer and heart disease and facilitate risk management and early cancer detection.

A molecular basis for neurofibroma-associated skeletal manifestations in NF1.

Genet Med

Plexiform neurofibromas (pNF) develop in children with neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown.

We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib.

We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib.

Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease.

Patient and family social media use surrounding a novel treatment for a rare genetic disease: a qualitative interview study.

Genet Med

Advances in gene therapy and precision medicine have led to a growing number of novel treatments for rare genetic diseases. Patients/families may lack access to up-to-date, accurate, and relevant information about these treatments. Social media offers one potentially important resource for these communities. Our goal was to understand how patients/families with spinal muscular atrophy (SMA)-a rare genetic condition-used social media to share, consume, and evaluate information about the novel treatment nusinersen (Spinraza) following the drug's approval.

We conducted qualitative, semistructured interviews with 20 SMA patients or parents of patients, deriving themes and subthemes through content and thematic network analysis. Participants also completed a demographic survey.

Participants described leveraging social media to learn about nusinersen treatment, make informed treatment decisions, and advocate for/access treatment. They also described critically evaluating the trustworthiness of nusinersen-related information on social media and the privacy risks of social media use.

Patients/families used social media to navigate the new and dynamic landscape of nusinersen treatment for SMA, while attempting to mitigate misinformation and privacy risks. As new treatments become available, providers and patients/families may benefit from proactively discussing social media use, so as to maximize important benefits while minimizing risks.

LncRNA SNHG17 promotes proliferation, migration and invasion of glioma cells by regulating the miR-23b-3p/ZHX1 axis.

J Gene Med

Long non-coding RNA (lncRNA) small nucleolar RNA host gene 17 (SNHG17) is a carcinogenic lncRNA in diverse cancers. Instead, the expression pattern and mechanisms of SNHG17 in glioma still await more verification.

Paired glioma samples were enrolled. SNHG17, miR-23b-3p and Zinc-fingers and homeoboxes 1 (ZHX1) mRNA expressions were examined by quantitative real-time polymerase chain reaction (qRT-PCR). SNHG17 shRNA and miR-23b-3p mimics were transfected into LN229 and U251 cell lines to repress SNHG17 and up-regulate miR-23b-3p expression, respectively. The proliferation, migration and invasion of LN229 and U251 cells were probed by cell counting kit-8 (CCK-8) assay and Transwell assay. Bioinformatics prediction, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, qRT-PCR and Western blot were applied to determine the regulatory relationships among SNHG17, miR-23b-3p and ZHX1.

SNHG17 expression was observably raised in glioma tissues, which was in positive correlation with ZHX1 expression and in negative association with the expression of miR-23b-3p. After the transfection of SNHG17 shRNAs into glioma cells, the proliferation, migration and invasion of cancer cells were markedly restrained. MiR-23b-3p mimics the function of SHNG17 knockdown. What's more, miR-23b-3p was proved to be negatively modulated by SNHG17, and ZHX1 was identified as a target of miR-23b-3p.

SNHG17 is a "competing endogenous RNA (ceRNA)" to modulate ZHX1 expression via adsorbing miR-23b-3p, thereby promoting the glioma progression.