Journal of Genetics and Genomics

Medical genetics: Towards precision medicine

Peng Jin

2018, 45(2): 55-56. doi: 10.1016/j.jgg.2018.02.005

Abstract (87) HTML PDF (2)

Abstract:

Turning the corner from observation to intervention in human genetics

David L. Nelson

2018, 45(2): 57-59. doi: 10.1016/j.jgg.2018.01.004

Abstract (58) HTML PDF (1)

Abstract:

Current strategies for the treatment of inborn errors of metabolism

Michael J. Gambello, Hong Li

2018, 45(2): 61-70. doi: 10.1016/j.jgg.2018.02.001

Abstract (82) HTML PDF (7)

Abstract:
Inborn errors of metabolism (IEMs) are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.

The current landscape for the treatment of mitochondrial disorders

Jesse Slone, Baoheng Gui, Taosheng Huang

2018, 45(2): 71-77. doi: 10.1016/j.jgg.2017.11.008

Abstract (74) HTML PDF (5)

Abstract:
The mitochondrial organelle is crucial to the energy metabolism of the eukaryotic cell. Defects in mitochondrial function lie at the core of a wide range of disorders, including both rare primary mitochondrial disorders and more common conditions such as Parkinson's disease and diabetes. Inherited defects in mitochondrial function can be found in both the nuclear genome and the mitochondrial genome, with the latter creating unique challenges in the treatment and understanding of disease passed on through the mitochondrial genome. In this review, we will describe the limited treatment regimens currently used to alleviate primary mitochondrial disorders, as well as the potential for emerging technologies (in particular, those involving direct manipulation of the mitochondrial genome) to more decisively treat this class of disease. We will also emphasize the critical parallels between primary mitochondrial disorders and more common ailments such as cancer and diabetes.

Genetic profiling of cancer with circulating tumor DNA analysis

Ling Lu, Junqin Bi, Liming Bao

2018, 45(2): 79-85. doi: 10.1016/j.jgg.2017.11.006

Abstract (80) HTML PDF (4)

Abstract:
Circulating cell-free tumor DNA (ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing (MPS), ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy. This review provides an overview of the latest development in our understanding of the biologic characteristics, detection methodologies, and potential clinical implications of ctDNA, as well as the challenges in translating ctDNA analysis from the research arena to patient care.

Developing DNA methylation-based diagnostic biomarkers

Hyerim Kim, Xudong Wang, Peng Jin

2018, 45(2): 87-97. doi: 10.1016/j.jgg.2018.02.003

Abstract (125) HTML PDF (8)

Abstract:
An emerging paradigm shift for disease diagnosis is to rely on molecular characterization beyond traditional clinical and symptom-based examinations. Although genetic alterations and transcription signature were first introduced as potential biomarkers, clinical implementations of these markers are limited due to low reproducibility and accuracy. Instead, epigenetic changes are considered as an alternative approach to disease diagnosis. Complex epigenetic regulation is required for normal biological functions and it has been shown that distinctive epigenetic disruptions could contribute to disease pathogenesis. Disease-specific epigenetic changes, especially DNA methylation, have been observed, suggesting its potential as disease biomarkers for diagnosis. In addition to specificity, the feasibility of detecting disease-associated methylation marks in the biological specimens collected noninvasively, such as blood samples, has driven the clinical studies to validate disease-specific DNA methylation changes as a diagnostic biomarker. Here, we highlight the advantages of DNA methylation signature for diagnosis in different diseases and discuss the statistical and technical challenges to be overcome before clinical implementation.

Precision medicine in hearing loss

Jason R. Rudman, Christine Mei, Sara E. Bressler, Susan H. Blanton, Xue-Zhong Liu

2018, 45(2): 99-109. doi: 10.1016/j.jgg.2018.02.004

Abstract (97) HTML PDF (1)

Abstract:
Precision medicine (PM) proposes customized medical care based on a patient's unique genome, biomarkers, environment and behaviors. Hearing loss (HL) is the most common sensorineural disorder worldwide and is frequently caused by a single genetic mutation. With recent advances in PM tools such as genetic sequencing and data analysis, the field of HL is ideally positioned to adopt the strategies of PM. Here, we review current and future applications of PM in HL as they relate to the four core qualities of PM (P4): predictive, personalized, patient-centered, and participatory. We then introduce a strategy for effective incorporation of HL PM into the design of future research studies, electronic medical records, and clinical practice to improve diagnostics, prognostics, and, ultimately, individualized patient treatment. Finally, specific anticipated ethical and economic concerns in this growing era of genomics-based HL treatment are discussed. By integrating PM principles into translational HL research and clinical practice, hearing specialists are uniquely positioned to effectively treat the heterogeneous causes and manifestations of HL on an individualized basis.

AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism

Chun Song, Han Yan, Hanming Wang, Yan Zhang, Huiqing Cao, Yiqi Wan, Lingbao Kong, Shenghan Chen, Hong Xu, Bingxing Pan, Jin Zhang, Guohuang Fan, Hongbo Xin, Zicai Liang, Weiping Jia, Xiao-Li Tian

2018, 45(2): 111-120. doi: 10.1016/j.jgg.2017.11.007

Abstract (76) HTML PDF (5)

Abstract:
Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream ofAQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3β, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.

2018 Vol. 45, No. 2