Current Genetic Medicine Reports

Abstract Purpose of Review Whole exome sequencing (WES) and whole-genome sequencing (WGS) are frontline approaches for the genetic diagnosis of rare diseases. However, WES/WGS fails in up to 75% of cases. Transcriptomics via RNA-sequencing (RNA-Seq) is a novel approach that aims to increase the diagnostic yield in rare diseases. Recent Findings Recent publications focus on the success of RNA-Seq for increasing diagnosis rates in WES/WGS-negative patients in up to 36% of cases, across a range of different diseases, sample sizes, and tissue types. Summary RNA-Seq is beneficial for aiding prioritisation of causative variants currently not detected or often overlooked by WES/WGS alone. An improvement in diagnostic yields has been demonstrated using multiple source tissues, with muscle and fibroblasts being the most representative, but the more accessible blood still demonstrating diagnostic success, particularly in neuromuscular disorders. The introduction of RNA-Seq to the genetic diagnosis toolbox promises to be a useful complementary tool to WES/WGS for improving genetic diagnosis in patients with rare disease.

Philippa D. K. Curry

Krystyna L. Broda

Christopher J. Carroll

The Role of RNA-Sequencing as a New Genetic Diagnosis Tool

RNA测序作为新型遗传诊断工具的作用

Siddharth Shah

Abiy Tereda

Hadeel M. Mansour

Molecular Mechanisms of Degeneration in Parkinson’s Disease; Deep Brain Stimulation, Pluripotent Stem Cell Therapy, and Cutting Edge Technology in Treatment Of Parkinson’s Disease

帕金森病退行性变的分子机制；深部脑刺激、多能干细胞疗法及帕金森病治疗的尖端技术

Over the last decade over 40 loci have been associated with risk of Alzheimer's disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action. Additionally, we recommend strategies for finding new protective variants.Recent Genome-Wide Association Studies have identified both common and rare protective variants associated with AD. These include variants in or near APP, APOE, PLCG2, MS4A, MAPT-KANSL1, RAB10, ABCA1, CCL11, SORL1, NOCT, SCL24A4-RIN3, CASS4, EPHA1, SPPL2A, and NFIC.There are very few protective variants with functional evidence and a derived allele with a frequency below 20%. Additional fine mapping and multi-omic studies are needed to further validate and characterize known variants as well as specialized genome-wide scans to identify novel variants.

Shea J. Andrews

Brian Fulton-Howard

Alison Goate

Protective Variants in Alzheimer’s Disease

阿尔茨海默病中的保护性变异

In this review we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3).Over the past five years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies.Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system and neuroinflammation, and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

Daniel W. Sirkis

Ethan G. Geier

Luke W. Bonham

Celeste M. Karch

Jennifer S. Yokoyama

Recent Advances in the Genetics of Frontotemporal Dementia

额颞叶痴呆遗传学的最新进展

It is well established that sporadic Alzheimer’s disease (AD) is polygenic with common and rare genetic variation alongside environmental factors contributing to disease. Here, we review our current understanding of the genetic architecture of disease, paying specific attention to rare susceptibility variants, and explore some of the limitations in rare variant detection and analysis. Rare variation has been shown to robustly associate with disease. These include potentially damaging and loss of function mutations that are easily modelled in silico, in vitro and in vivo, and represent potentially druggable targets. A number of risk genes, including TREM2, SORL1 and ABCA7 show multiple independent associations suggesting that they may influence disease via multiple mechanisms. With transcriptional regulation, inflammatory response and modification of protein production suggested to be of primary importance. We are at the beginning of our journey of rare variant detection in AD. Whole exome sequencing has been the predominant technology of choice. While fruitful, this has introduced a number of challenges with regard to data integration. Ultimately the future of disease-associated rare variant identification lies in whole genome sequencing projects that will allow the testing of the full range of genomic variation.

Detelina Grozeva

Salha Saad

Georgina E. Menzies

Rebecca Sims

Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

阿尔茨海默病中罕见遗传变异的益处与挑战

Leifan Wang

Xiaohui Liang

Al-Accelerated Human Genetic Discrimination: Implications of UNGPs

铝加速人类遗传歧视：联合国工商业与人权指导原则的启示

Geoffrey Otim

Sandra Matinyi

Ian Peter Busuulwa

Perez Mweine

Erikan Baluku

George Peter Magoola

Ivy S. G. Chimulwa

Stephen Mukuze

Peace Proscovia Aber

Peter Ahabwe Babigumira

Alex Katumba

Stephen Obol Opiyo

Addressing Gene Modified Technology for Emerging Risks Through Regional Networks

短名	Curr. Genet. Med. Rep.
Journal Impact	1.50
国际分区	GENETICS & HEREDITY(Q4)

出版信息	出版商: Springer Science and Business Media LLC，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: ，原创研究文献占比: ，自引率:， Gold OA占比: 37.50

Current Genetic Medicine Reports

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The Role of RNA-Sequencing as a New Genetic Diagnosis Tool

Molecular Mechanisms of Degeneration in Parkinson’s Disease; Deep Brain Stimulation, Pluripotent Stem Cell Therapy, and Cutting Edge Technology in Treatment Of Parkinson’s Disease

Protective Variants in Alzheimer’s Disease

Recent Advances in the Genetics of Frontotemporal Dementia

Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

Molecular Mechanisms of Degeneration in Parkinson’s Disease; Deep Brain Stimulation, Pluripotent Stem Cell Therapy, and Cutting Edge Technology in Treatment Of Parkinson’s Disease

Al-Accelerated Human Genetic Discrimination: Implications of UNGPs

Addressing Gene Modified Technology for Emerging Risks Through Regional Networks

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