Article

Human Genome Sequencing in Health and Disease

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Annual review of medicine (Impact Factor: 12.93). 02/2012; 63(1):35-61. DOI: 10.1146/annurev-med-051010-162644
Source: PubMed

ABSTRACT

Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.

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Available from: Claudia Gonzaga-Jauregui, Dec 17, 2013
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    • "Genomic approaches to diagnosis include array comparative genomic hybridization (aCGH), whole genome sequencing (WGS) and WES. These approaches have identified the genetic etiology of many diverse Mendelian diseases[14]. Recently, large-scale WES studies have been conducted on a number of NDD cohorts151617181920. "
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    ABSTRACT: Background: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay. Methods: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members. Results: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss. Conclusions: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.
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    • "Genomic sequencing is a successful strategy for the diagnosis of rare inherited disorders[5,17,29]. In addition to gene discovery, sequencing can identify mutations in known disease genes, particularly when the phenotype is unusual or atypical compared to previously reported cases. "
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    ABSTRACT: We present a patient with a unique neurological phenotype with a progressive neurodegenerative. An 18-year diagnostic odyssey for the patient ended when exome sequencing identified a homozygous PEX16 mutation suggesting an atypical peroxisomal biogenesis disorder (PBD). Interestingly, the patient's peroxisomal biochemical abnormalities were subtle, such that plasma very-long-chain fatty acids initially failed to provide a diagnosis. This case suggests that next-generation sequencing may be diagnostic in some atypical peroxisomal biogenesis disorders.
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    • "In this context, " constitution " includes the body's structural and functional features, including psychological characteristics [4]. Current genetic science has shown that the genome critically affects the complex processes involved in health and disease [5], and the SCM classification is presumably related to macrolevel genomic differences among individuals [6]. "
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