The Practice and Exploration of Applying EBM to Bilingual Teaching of Medical Genetics at OSBCM

In the process of teaching medical genetics of undergraduate clinical medicine, the practice and exploration of applying EBM to the bilingual teaching of OSBCM medical genetics are carried out. Using CBL and PBL as the carrier can make up for the shortcomings of a single teaching mode, synthesize the advantages of multiple teaching modes. It starts from integrating the basic theoretical knowledge of medicine and clinical practice knowledge, improving students’ bilingual level of medical genetics, cultivating students’ literature retrieval ability, and promoting early clinical, multi-clinical and repeated clinical consciousness for medical students. Therefore, it is more conducive to cultivate students’ ability to learn independently, accurately analyze and solve problems, improve medical students’ clinical thinking ability and scientific research awareness, improve medical students’ ability of international communication, and lay a solid foundation for improving medical students’ future post competence, innovative spirit and lifelong learning ability.

PROSPECT OF MEDICAL GENETICS IN CHINA FROM A HISTORICAL POINT OF VIEW

The history of medical genetics is briefly reviewed. It is evident that medical genetics with its inseparable part, clinical genetics, started out as a cfinical science from the very beginning. Its robust development in the developed countries is the result of a close interaction between the basic sciences and clinical genetics. In China, however, clinical genetics has not received due emphasis and medical genetics is still not recognized as one of the medical specialties. This is in marked contrast to the situation in the West. It is high time to acknowledge that medical genetics is a medical specialty and to promote clinical genetics service in qualified hospitals in our country.

The forty years of medical genetics in China

Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy,Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a wellconstructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection,along with strong support at the national industry level.

Medical genetics:Towards precision medicine

Medical genetics is defined as a branch of medicine that involves the diagnosis and management of hereditary disorders by applying genetics to medical care.The Human Genome Project,initiated in1990 and completed in 2004,has profoundly changed biology and is rapidly catalyzing a transformation of medical genetics and medicine in general（Collins and McKusick,2001;Green and Guyer,2011）.

Progress and challenges in CRISPR-mediated therapeutic genome editing for monogenic diseases

There are an estimated 10000 monogenic diseases affecting tens of millions of individuals worldwide.The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients.CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA.The complexity of genomic insults resulting in heritable disease requires patientspecific genome editing strategies with consideration of DNA repair pathways,and CRISPR/Cas systems of different types,species,and those with additional enzymatic capacity and/or delivery methods.In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair,non-homologous end joining,microhomology-mediated end joining,and base editing to permanently correct diverse monogenic diseases.

Genomics in medicine: A new era in medicine

The sequencing of complete human genome revolutionized the genomic medicine.However,the complex interplay of gene-environment-lifestyle and influence of non-coding genomic regions on human health remain largely unexplored.Genomic medicine has great potential for diagnoses or disease prediction,disease prevention and,targeted treatment.However,many of the promising tools of genomic medicine are still in their infancy and their application may be limited because of the limited knowledge we have that precludes its use in many clinical settings.In this review article,we have reviewed the evolution of genomic methodologies/tools,their limitations,and scope,for current and future clinical application.

Profile of Patients Attended at the Genetic Service of a Special Care Institution in Brazil

Objective： To analyze the main etiological diagnoses of patients attended at a genetics outpatient clinic of the Association of Parents and Friends of Exceptional Children/APAE in the state of Amazonas, Brazil. Methods： retrospective study of patients seen in the period 2005-2016, with review of medical records. The following data were recorded： sex, origin of referral and etiological diagnosis. Results： 362 patients were attended, 94.7% of them from Manaus, and 5.3% from the interior of the state. The etiological diagnosis was defined in 262 （72.3%） of the sample, of which 254 （70.2%） were of genetic etiology and 8 （2.2%） non-genetic. Of the genetic etiologies, 46 （12.7%） cases were monogenic syndromes, 136 （37.6%） were chromosomal aberrations and 72 （19.9%） had multifactorial causes, however, 100 （27.6%） cases remained unclear. There were several syndromes found, with Down syndrome being the most frequent and correlating significantly with the sex of the patient （male predominance, p 〈 0.05）. Conclusions： The study carried out in the APAE/Manaus genetics outpatient clinic allowed the profile of the patients being attended to be traced. It was verified that the majority of the patients were male and that the diagnosis of chromosomal alterations was the most frequent.

The impact of codon 54 variation in intestinal fatty acid binding protein gene on the pathogenesis of diabetes mellitus in Chinese

Objective To investigate whether or not the intestinal fatty acid binding protein gene (FABP2) Ala54Thr variation is related to non insulin dependent diabetes mellitus (NIDDM), obesity, dyslipidemia and glucose stimulated insulin secretion (GSIS) in Chinese.Methods The FABP2 Ala54Thr variation was detected by PCR/HhaI digestion in 231 Chinese subjects (116 with normal glucose tolerance (NGT), 54 with impaired glucose tolerance (IGT) and 61 with NIDDM). Plasma glucose, insulin and C peptide levels before and after 75 g glucose load as well as fasting lipid profile were determined.Results (1) The Ala54 and Thr54 allele frequencies in Chinese were 0.71 and 0.29 respectively; (2) The FABP2 Ala54Thr variation was neither associated with fasting and post challenged plasma glucose levels nor with NIDDM; (3) This variation was neither associated with fasting lipid profile nor with obesity; (4) The IGT subjects with genotype Thr54(+) (Thr54 homozygotes and heterozygotes) had lower fasting, 2 hour and total C peptide levels and smaller AUC representing lesser C peptide secretion after glucose challenge than those with genotype Thr54( ) (Ala54 homozygotes) (P= 0.04 , 0.03, 0.01 and 0.01 respectively). The serum insulin levels changed in the same tendency.Conclusions The glucose stimulated insulin secretion (GSIS) reserve of islet beta cells is more limited in subjects with FABP2 Thr54(+) genotype than in those with FABP2 Thr54(-) genotype. It suggests that FABP2 codon 54 variation might contribute to the insufficient insulin secretion in the development of NIDDM in Chinese.

Reproductive medicine and congenital heart disease

With the development of medical genetics,reproductive medicine has made considerable contributions to treatment of birth defects,a reduction in the incidence of birth defects,implementation of eugenics and fertility,and improvement of population quality.Congenital heart disease is a common birth defect and is the most serious among all birth defect diseases and seriously endangers the physical and mental health of children in China.In this article,we review the latest research progress of congenital heart disease in the field of reproduction.

Identification of mutation in a candidate gene for hereditary multiple exostoses type Ⅱ

Objectives To identify possible mutations in our previously cloned candidate gene for hereditary multiple exostoses type Ⅱ (EXT2) in affected members of EXT families so as to confirm that it is the disease causing gene. Methods The mutation was detected first by single strand conformational polymorphism(SSCP) of all coding exons of the candidate gene and then by sequencing analysis. Results After analyzing 37 patients from 20 Chinese EXT families by SSCP and DNA sequencing analysis, one 2 bp insertion mutation was identified in this candidate gene in affected members of an EXT family. This mutation resulted in the frameshift and generated a truncated gene product consisting of 105 amino acids. Conclusions The identification of the mutation in the candidate gene indicates that this novel gene is responsible for EXT2 (one of the disease causing gene of EXT).

Reversal of aberrant splicing of β-thalassemia allele by antisense RNA in vitro and in vivo

Objective To investigate the reversal of aberrant splicing of β thalassemia allele (IVS 2 654 C→T, β 654 ) by antisense RNA in vitro and in vivo.Methods The vector expressing antisense RNA which targeted against the aberrant splice sites of β 654 pre mRNA was constructed in pcDNA3, and then used to repair the defective splicing of the mutant pre mRNA in an in vitro transcription and splicing system, as well as in HeLa β 654 cells and cultured β 654 erythroid cells by lipid mediated DNA transfection method. The effect of the antisense RNA was identified by RT PCR mediated mRNA quantitative assay as well as globin chain micro biosynthesis.Results The antisense RNA decreased the aberrant splicing product and restored the correct splicing pattern in vitro and in vivo efficiently. In the in vitro transcription and splicing system, the level of normally spliced mRNA [β/(β+β *)] increased from 0.25 to 0.60. In cultured HeLa β 654 cells, the level of β/(β+β *) increased from 0.07 to 0.43 on the 15th day after transfection. In cultured β 654 erythroid cells, the level of mRNA [β/(β+β *)] increased from 0.19 to 0.58 on the 8th day after transfection in β 654 /β 654 erythroid cells, from 0.02 to 0.38 in β 654 /β 41 42 erythroid cells, and from 0.45 to 0.83 in β 654 /βA erythroid cells, respectively. Correspondingly, the ratios of globin chain (β/α) biosynthesis increased from 0.16 to 0.52 on the 8th day after transfection in β 654 /β 654 erythroid cells, 0.05 to 0.36 in β 654 /β 41 42 erythroid cells, and 0.42 to 0.81 in β 654 /β A erythroid cells, respectively. The splicing pattern did not show significant changes as compared to the untreated, as well as to the control antisense fragment.Conclusions Antisense RNA transcribed from the expression vector described here could efficiently suppress the aberrant splicing pattern of β 654 mutant mRNA and restore the correct splicing pathway in vitro and in vivo, leading to the improvement of globin chain biosynthesis in thalassemic cells. Our antisense strategy provides an alternative approach to the gene therapy of β thalassemia.