Field Of Medical Genetics Research Articles

Integrating deep phenotyping with genetic analysis: a comprehensive workflow for diagnosis and management of rare bone diseases.

Phenotypes play a fundamental role in medical genetics, serving as external manifestations of underlying genotypes. Deep phenotyping, a cornerstone of precision medicine, involves precise multi-system phenotype assessments, facilitating disease subtyping and genetic understanding. Despite their significance, the field lacks standardized protocols for accurate phenotype evaluation, hindering clinical comprehension and research comparability. We present a comprehensive workflow of deep phenotyping for rare bone diseases from the Genetics Clinic of Skeletal Deformity at Peking Union Medical College Hospital. Our workflow integrates referral, informed consent, and detailed phenotype evaluation through HPO standards, capturing nuanced phenotypic characteristics using clinical examinations, questionnaires, and multimedia documentation. Genetic testing and counseling follow, based on deep phenotyping results, ensuring personalized interventions. Multidisciplinary team consultations facilitate comprehensive patient care and clinical guideline development. Regular follow-up visits emphasize dynamic phenotype reassessment, ensuring treatment strategies remain responsive to evolving patient needs. In conclusion, this study highlights the importance of deep phenotyping in rare bone diseases, offering a standardized framework for phenotype evaluation, genetic analysis, and multidisciplinary intervention. By enhancing clinical care and research outcomes, this approach contributes to the advancement of precision medicine in the field of medical genetics.

Genetic diseases are not necessarily inherited: suggestion on its Chinese translation.

From Mendel's discovery of the basic laws of genetics in 1865 to the widespread application of genomics in medicine today, medical genetics has made enormous progress, and the concept of genetic diseases has also been evolved. In 1972, the World Health Organization (WHO) expert group began to use "Genetic Disease" to define hereditary diseases, while early Chinese genetics textbooks used "inferior inheritance", and later introduced terms such as "Genetic Disease" and "Inherited Disease". In the early days, it was generally believed that genetic diseases were inherited from ancestors. However, research in recent years has found that genetic diseases are not necessarily inherited, and some diseases are actually caused by de novo mutations in the offspring. Although the occurrence of this type of genetic disease is related to genetic factors, it is not inherited from ancestors. If we still use "Inherited Disease" or "Hereditary Disease" to describe it, it is not accurate enough. In order to further standardize the translation and use of the concept of "Genetic Disease", this article briefly reviews its development process in both English and Chinese literature, discusses the difference between different Chinese translations, and provides guidance and suggestions for scientifically and accurately describing genetic diseases in Chinese, with a view to promote efficient exchange and cooperation in the field of medical genetics.

Is artificial intelligence getting too much credit in medical genetics?

Artificial intelligence has lately proven useful in the field of medical genetics. It is already being used to interpret genome sequences and diagnose patients based on facial recognition. More recently, large-language models (LLMs) such as ChatGPT have been tested for their capacity to provide medical genetics information. It was found that ChatGPT performed similarly to human respondents in factual and critical thinking questions, albeit with reduced accuracy in the latter. In particular, ChatGPT's performance in questions related to calculating the recurrence risk was dismal, despite only having to deal with a single disease. To see if challenging ChatGPT with more difficult problems may reveal its flaws and their bases, it was asked to solve recurrence risk problems dealing with two diseases instead of one. Interestingly, it managed to correctly understand the mode of inheritance of recessive diseases, yet it incorrectly calculated the probability of having a healthy child. Other LLMs were also tested and showed similar noise. This highlights a major limitation for clinical use. While this shortcoming may be solved in the near future, LLMs may not be ready yet to be used as an effective clinical tool in communicating medical genetics information.

An integrative analysis of genotype-phenotype correlation in Charcot Marie Tooth type 2A disease with MFN2 variants: A case and systematic review

Dominant genetic variants in the mitofusin 2 (MFN2) gene lead to Charcot-Marie-Tooth type 2A (CMT2A), a neurodegenerative disease caused by genetic defects that directly damage axons. In this study, we reported a proband with a pathogenic variant in the GTPase domain of MFN2, c.494A > G (p.His165Arg). To date, at least 184 distinct MFN2 variants identified in 944 independent probands have been reported in 131 references. However, the field of medical genetics has long been challenged by how genetic variation in the MFN2 gene is associated with disease phenotypes. Here, by collating the MFN2 variant data and patient clinical information from Leiden Open Variant Database 3.0, NCBI clinvar database, and available related references in PubMed, we determined the mutation frequency, age of onset, sex ratio, and geographical distribution. Furthermore, the results of an analysis examining the relationship between variants and phenotypes from multiple genetic perspectives indicated that insertion and deletions (indels), copy number variants (CNVs), duplication variants, and nonsense mutations in single nucleotide variants (SNVs) tend to be pathogenic, and the results emphasized the importance of the GTPase domain to the structure and function of MFN2. Overall, three reliable classification methods of MFN2 genotype-phenotype associations provide insights into the prediction of CMT2A disease severity. Of course, there are still many MFN2 variants that have not been given clear clinical significance, which requires clinicians to make more accurate clinical diagnoses.

Experience in Implementing ISO 15189:2012 Accreditation at Chimera Transplant Research Foundation: A Molecular Testing Laboratory

ISO15189:2012 is a formal recognition by an authorized national accreditation body that a testing laboratory is competent to carry out specific tasks according to the standard. This article aims to share the experience of reaching ISO 15189:2012 accreditation at Chimera labs. A gap analysis was performed, followed by the preparation and implementation of policies and procedures for the effective implementation of QMS. After six months of intensive work, including mentoring activities, the laboratory was ISO 15189 accredited in the field of medical genetics and related HLA and immunogenetics by the National Accreditation Board for Testing and Calibration Laboratories, India. Our experience suggests that the implementation of a quality management system is possible even in small-sized laboratories with the help of skilled manpower and supportive management.

Paternal half-sisters or unrelated – How can the X-chromosomal evidence be quantified when one female presents trisomy X?

The X chromosome has unique features, such as haplodiploid mode of genetic transmission, which can be crucial to complement autosomal profiling or to disentangle complex kinship problems. Indeed, for some cases (e.g. full- or paternal half-sisters, or paternal grandmother-granddaughter hypotheses), X-markers are expected to provide a similar or a higher power to the one obtained with autosomes in paternity/maternity investigations. Both theoretical and informatics frameworks for pairwise X-linked kinship analyses are well established for individuals with a regular number of chromosomes, but these are still lacking for individuals exhibiting an X chromosome aneuploidy, such as females with Triple X (47, XXX) syndrome. Indeed, this work was motivated by a real forensic case involving the evaluation with X-chromosomal markers of the hypotheses that two women were related either as paternal half-sisters or as unrelated, one of them showing a trisomy X. In this case, the analysis of X-chromosomal markers would yield stronger results than autosomes, as females had to share at least one identical allele in each analyzed X chromosome marker under the paternal half-sibling hypothesis, unless a mutation occurs. To fulfill this gap, we present in this work algebraic formulae for some genotypic configurations, which will allow quantification of the evidence on the referred cases. A general approach, comprising other X chromosome aneuploidies, kinship hypotheses, and genotypic configurations, is currently being developed by us. This work is the starting point to analyze X-chromosomal data under the scope of kinship problems, involving individuals with aneuploidies. This will improve the quantification of DNA evidence not only in forensic casework, but also in the field of medical genetics, whenever individuals with X-chromosomal aneuploidies are involved.

Translating principles of precision medicine into speech-language pathology: Clinical trial of a proactive speech and language intervention for infants with classic galactosemia.

SummaryPrecision medicine is an emerging approach to managing disease by taking into consideration an individual’s genetic and environmental profile toward two avenues to improved outcomes: prevention and personalized treatments. This framework is largely geared to conditions conventionally falling into the field of medical genetics. Here, we show that the same avenues to improving outcomes can be applied to conditions in the field of behavior genomics, specifically disorders of spoken language. Babble Boot Camp (BBC) is the first comprehensive and personalized program designed to proactively mitigate speech and language disorders in infants at predictable risk by fostering precursor and early communication skills via parent training. The intervention begins at child age 2 to 5 months and ends at age 24 months, with follow-up testing at 30, 42, and 54 months. To date, 44 children with a newborn diagnosis of classic galactosemia (CG) have participated in the clinical trial of BBC. CG is an inborn error of metabolism of genetic etiology that predisposes up to 85% of children to severe speech and language disorders. Of 13 children with CG who completed the intervention and all or part of the follow-up testing, only one had disordered speech and none had disordered language skills. For the treated children who completed more than one assessment, typical speech and language skills were maintained over time. This shows that knowledge of genetic risk at birth can be leveraged toward proactive and personalized management of a disorder that manifests behaviorally.

Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation

SUMMARYThe dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide “lumping and splitting” decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.

Preimplantation Genetic Testing: A Review of Past and Current

The field of medical genetics has seen significant and incredible advances in technology for the past several decades. Genetic technologies, particularly in the reproductive medicine discipline, represent a fresh era in medicine that may develop significantly in the coming years. The purpose of Preimplantation Genetic Testing (PGT) in the situation of assisted reproductive technology (ART) treatments with IVF (in vitro fertilization) or ICSI (intracytoplasmic sperm injection) is particularly controversial as it is done before implantation [1]. However, despite the successful application of PGT in the field of IVF in overcoming infertility and genetic defects, the techniques pose various limitations, and concerns that need to be addressed to enhance their success rate [2]. This review will introduce PGT and summarize the molecular techniques used in its application as well as highlight the future advances in the field.

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer.

Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.

Genetics-Related Activities in Everyday Practice of Family Physicians in Slovenia

Introduction: Development of genomic technologies has an important impact on patient management in medicine. Nevertheless, translation of new advances of genomic medicine in primary care is challenging and needs to be adapted to the needs of health systems. Objective: The objective of this study was to analyze the current state of the use and the level of confidence in genetic management activities in everyday clinical practice of family practitioners (FPs) in Slovenia. Methods: We used a cross-sectional observational study design. The dataset was obtained through a questionnaire containing demographics, questions about the use of genetics in everyday practice, and a scale for measuring the responders’ confidence in their ability to carry out basic genetic activities during patient treatment. The questionnaire was sent by regular mail to every FP in Slovenia (N = 950). Results: The questionnaire was completed by a total of 271 physicians (response rate 28.5%), with an average physicians’ age of 45.5 ± 10.6 years. In their everyday clinical practice, the majority of Slovenian FPs report to encounter genetic conditions more than once a month (241, 91.2%). Family medical history is the most commonly used among all activities related to genetic management of patients. Only 5.9% of Slovenian FPs are confident in their ability to carry out basic activities related to genetic patient management. Most of them believe they are only competent enough to obtain family medical history and identify a positive family history. The FPs who reported a lower degree of confidence are those with the lowest level of education in the field of medical genetics and older physicians (age >50 years). Conclusions: Slovenian family physicians commonly encounter patients with genetic conditions but are not confident in their ability to carry out basic medical genetic tasks. Therefore, additional education is necessary.

NEED OF GENETIC COUNSELING SERVICES AT DISTRICT D.I.KHAN

Genetic counseling is an advocating strategy based on family history and genetic testing results, in order to avoid inherited disorders and their transmission to next generation.1 For the first time Sarah Lawrence College at New York offered the first master’s level training course of genetic counseling in 1969. According to a recent estimate, seven thousand genetic counsellors in 28 different countries are offering their services in the field of medical genetics.4 Now-a-days, in the era of advance genomics, the genetic counseling services became more specialized as cancer genetics, cardiogenetics, neurogenetics, infertility genetics and other speciality areas. The clinical implementation of genetic counseling services in US, Canada, and European countries is well established. However, in Asia these only exist in India, Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Taiwan and few Middle Eastern countries.4 As far as Pakistan is concerned, it is still in infancy in Pakistan, requiring great improvements to be done. Genetic counseling services are the dire need of those countries where consanguineous marriages are highly prevalent so as to reduce the burden of genetic disorders and improve the quality of life.2 Pakistan is one among those countries which has alarming rate of consanguineous marriages, especially first cousin unions.3 However, within Pakistan, Khyber-Pukhtunkhwa, including D.I.Khan division has comparatively high ratio of close familial marriages. Currently, D.I.Khan is inhabited by multi-ethnic population of local as well as those migrated from South Waziristan and other adjoining tribal areas. According to a non-documented evidence, it is observed that cancer, type-2 diabetes, thalassemia, cataract, and certain neurological disorders have high occurrence in these people. World Health Organization (WHO), in its report, has observed that genetic counseling services in developing countries are inadequate, and advised the governments to ensure, their availability as part of their healthcare systems.3,4 Keeping in view this scenario, D.I.Khan requires to establish a genetic counseling centre. It is proposed to set up genetic counseling centre with the mutual collaboration of Gomal University and Gomal Medical College, D.I.Khan that should advise the people regarding disease carrier testing, pharmacogenetics testing, pre-natal testing and pre-symptomatic testing. We also propose that each tertiary care hospital should engage a genetic counsellor to prevent the incidence of genetic disorders, select the best personalized medicine and pre-symptomatic management of disease.

Growth of interest to research in the field of medical genetics according to the analysis of scientific publications

Growth of interest to research in the field of medical genetics according to the analysis of scientific publications

Abstract TP161: The Cerebrovascular Disease Knowledge Portal: an Open Access Data Resource to Accelerate Genomic Discoveries in Stroke

Introduction: High throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. Open data access is the final barrier capitalizing fully on the opportunities available in stroke genetics research. The International Stroke Genetics Consortium (ISGC) has created the Cerebrovascular Disease Knowledge Portal (CDKP), a platform to explore and access genetic data related to cerebrovascular diseases. Methods: Funded by the NIH, the CDKP has been developed by the ISGC and the American Heart Association (AHA) Institute for Precision Cardiovascular Medicine. The CDKP seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on patients with stroke. Within the CDKP, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. Any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. Results: The CDKP houses two types of data, for different regulatory and analytical needs: summary level data and individual level data. The CDKP offers three main features: (1) a web-based graphical user interphase that allows the exploration of genomic information through a wide menu of integrated tools for analysis and data visualization; (2) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field; and (3) a repository of individual level data, accessible through a secure cloud working space provided by the AHA Platform for Precision Medicine. The CDKP can be accessed at www.cerebrovascularportal.org . Conclusion: The CDKP advances the ISGC’s goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. In the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well.

Genetics and genomic medicine in Cuba.

Genetics and genomic medicine in Cuba.

GARLIC: a bioinformatic toolkit for aetiologically connecting diseases and cell type-specific regulatory maps.

Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70–90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type-specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease-causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders.

From big biological data to big discovery: The past decade and the future

The quick accumulation of biological and medical big data is an important characteristic of current life sciences. Typical representatives of such big data are omics data obtained with the so-called next-generation sequencing or NGS technology, including genomic data, epigenomic data, metagenomic data, transcriptomics data, etc. The amount of data is overwhelming, but our key interest is whether such big data can lead to big discovery on the rules or mechanisms behind life. The question “how will big pictures emerge from a sea of biological data” was asked as one of the 125 most challenging questions by the Science magazine in 2005. Now more than ten years have passed. This article provides a brief review and perspective on the development of next-generation DNA sequencing technology in the past decade, as well as its applications and impacts on the fields of medical genetics, synthetic biology, precision medicine and microbiome studies. The big biological data have already brought new discoveries in biology although yet more will be expected and such discoveries have already shown promising applications in medical practices. The wide availability of DNA sequencing especially its rapidly decreasing cost is revolutionizing the study of genetic diseases. Large-scale genome-wide association studies (GWAS) and exome-sequencing studies have discovered many genes that are associated with many types of diseases. Some have already began to be used in clinical diagnosis. Accompanying the development of technologies for reading genomes, the genome editing technology shows the other side of the story: editing and writing genomes. Such technologies are enabling the systematic understanding of complex biological systems, and point to promising new approaches for disease treatment and prevention. Cancer studies are a major field that benefited the most from omics data. People are gaining more and more understanding in the development of cancer, and new taxonomy of cancer types based on genomic and epigenomic data brings the hope toward the goal of precision medicine. NGS also brought big data of metagenome of human microbiomes. Such data have revealed the importance of microbiota to many aspects of human health. Big biological data have brought many advancement in life sciences and will lead to more scientific breakthroughs in the future. To achieve this, bioinformatics has been playing a major role in turning data to information, and turning information to knowledge. Omics data are only type of the data for human health. Phenotypical data including data in medical records are equally or more important. It can be expected that the integrative analyses of omics data and medical phenotype data will bring more new discoveries for precision medicine research and practice. Methodology research on integrating and mining big biological and medical data will be crucial for such discoveries.

Research advances on medical genetics in China in 2015

Steady progress has been achieved in the medical genetics in China in 2015, as numerous original researches were published in the world's leading journals. Chinese scientists have made significant contributions to various fields of medical genetics, such as pathogenicity of rare diseases, predisposition of common diseases, somatic mutations of cancer, new technologies and methods, disease-related microRNAs (miRNAs), disease-related long non-coding RNAs (lncRNAs), disease-related competing endogenous RNAs (ceRNAs), disease-related RNA splicing and molecular evolution. In these fields, Chinese scientists have gradually formed the tendency, from common variants to rare variants, from single omic analyses to multipleomics integration analyses, from genetic discovery to functional confirmation, from basic research to clinical application. Meanwhile, the findings of Chinese scientists have been drawn great attentions of international peers. This review aims to provide an overall picture of the front in Chinese medical genetics, and highlights the important findings and their research strategy.

Buggies, villi, cornelia, and genes: My extended mentorship with LG Jackson.

Although Laird G. Jackson, M.D., has mentored many individuals, most in the field of Medical Genetics, he remains inspirational and true to his basic tenets. This invited comment describes how he shaped the professional course of one of his "mentees." © 2016 Wiley Periodicals, Inc.

Future Implications of Human Embryonic Testing and Modification: Great Medicine or GATTACA?

The past several decades have seen tremendous advances in the field of medical genetics. Currently, the application of genetic testing on human embryos determines if embryos harbor a lethal condition or a serious genetic disease. The purpose of this sort of testing is not to "improve" the offspring of a couple. Rather, current testing strategies focus on helping couples to have a healthy family in an efficient manner. Newly emerging technologies have opened the door to test embryos for an exponentially growing number of traits. Additionally, recent reports describe the actual modification of human embryonic DNA. The implications from the application of this technology are many and have the potential to fundamentally change the social paradigm of the human experience. Embryonic testing and modification does have the potential to accomplish good and is not inherently amoral. However, thoughtful consideration should be given by scientists, legislators, and the general population on how to apply this technology in a manner that is both appropriate and equitable and does not result in further social stratification and polarization, both within individual nations and the global community.