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: 15.48). 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 rearrangements represent a class of DNA variations (deletion, duplication, insertion, inversion, translocation) ranging in size from hundreds to millions of bp and cause both Mendelian and complex disorders (reviewed by [Chen et al., 2010; Girirajan et al., 2011; Gonzaga-Jauregui et al., 2012; Liu et al., 2012; Simmons et al., 2012]). Genomic rearrangements originally were thought to be randomly distributed among the human genome. "
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    ABSTRACT: Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197 bp long palindromic AT-rich repeat (PATRR17) is located within intron 40 of the neurofibromatosis type 1 (NF1) gene (17q11.2). Through comprehensive NF1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR17 may be involved in these rearrangements thereby causing NF1. Breakpoint cloning revealed that PATRR17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR17 partner breakpoints were located within 7.1 kb upstream of PATRR17, fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR) was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR17, proximal to the breakpoint, suggesting a multiple stalling and re-replication process, in contrast to previous studies indicating a purely replication-independent mechanism for PATRR-mediated translocations. In conclusion, we show evidence that PATRR17 is a hotspot for pathogenic intragenic deletions within the NF1 gene and suggest a novel replication-dependent mechanism for PATRR-mediated translocation.This article is protected by copyright. All rights reserved
    Human Mutation 07/2014; 35(7). DOI:10.1002/humu.22569 · 5.05 Impact Factor
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    • "Researchers and physicians have extensively discussed the benefits and risks associated with the introduction of WES/ WGS in clinical practice (Brunham and Hayden 2012; Gonzaga-Jauregui et al. 2012; Hastings et al. 2012; Lerner- Ellis 2012). Select studies have identified the need for appropriately trained professionals who are skilled at interpreting and translating the data to consent participating individuals (Brunham and Hayden 2012). "
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    ABSTRACT: In recent years, new sequencing technologies known as next generation sequencing (NGS) have provided scientists the ability to rapidly sequence all known coding as well as non-coding sequences in the human genome. As the two emerging approaches, whole exome (WES) and whole genome (WGS) sequencing, have started to be integrated in the clinical arena, we sought to survey health care professionals who are likely to be involved in the implementation process now and/or in the future (e.g., genetic counselors, geneticists and nurse practitioners). Two hundred twenty-one genetic counselors- one third of whom currently offer WES/WGS-participated in an anonymous online survey. The aims of the survey were first, to identify barriers to the implementation of WES/WGS, as perceived by survey participants; second, to provide the first systematic report of current practices regarding the integration of WES/WGS in clinic and/or research across the US and Canada and to illuminate the roles and challenges of genetic counselors participating in this process; and third to evaluate the impact of WES/WGS on patient care. Our results showed that genetic counseling practices with respect to WES/WGS are consistent with the criteria set forth in the ACMG 2012 policy statement, which highlights indications for testing, reporting, and pre/post test considerations. Our respondents described challenges related to offering WES/WGS, which included billing issues, the duration and content of the consent process, result interpretation and disclosure of incidental findings and variants of unknown significance. In addition, respondents indicated that specialty area (i.e., prenatal and cancer), lack of clinical utility of WES/WGS and concerns about interpretation of test results were factors that prevented them from offering this technology to patients. Finally, study participants identified the aspects of their professional training which have been most beneficial in aiding with the integration of WES/WGS into the clinical setting (molecular/clinical genetics, counseling and bioethics) and suggested that counseling aids (to assist them when explaining aspects of these tests to patients) and webinars focused on WES/WGS (for genetic counselors and other health care professionals) would be useful educational tools. Future research should permit us to further enhance our knowledge of pitfalls and benefits associated with the introduction of these powerful technologies in patient care and to further explore the roles and opportunities for genetic counselors in this rapidly evolving field.
    Journal of Genetic Counseling 03/2014; 23(4). DOI:10.1007/s10897-014-9709-4 · 1.75 Impact Factor
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    • "stdev, standard deviation. a valuable tool for mutation identification in rare and genetically heterogeneous disorders [Bamshad et al., 2011; de Ligt et al., 2012; Gilissen et al., 2012; Gonzaga-Jauregui et al., 2012; Hanchard et al., 2013; Ng et al., 2010; O'Roak et al., 2012; Rauch et al., 2012]. For example, in a genetically heterogeneous disorder such as ID, a causal or candidate (de novo) mutation was identified in up to 38% of cases [de Ligt et al., 2012; Rauch et al., 2012], and it has been reported that an additional 10%–20% of ID cases can be explained by clinically relevant de novo CNVs [Mefford et al., 2012]. "
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    ABSTRACT: Copy number variation (CNV) is a common source of genetic variation that has been implicated in many genomic disorders. This has resulted in the widespread application of genomic microarrays as a first tier diagnostic tool for CNV detection. More recently whole exome sequencing (WES) has proven successful for the detection of clinically relevant point mutations and small insertion-deletions exome-wide. We evaluate the utility of short read WES (SOLiD 5500xl) to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth analysis of WES data; a heterozygous single-exon deletion remained undetected by all algorithms evaluated. Although the detection power of WES for small CNVs currently does not match that of high-resolution microarray platforms, we show that the majority (88%) of rare coding CNVs containing three or more exons are successfully identified by WES. These results show that the CNV detection resolution of WES is comparable to that of medium resolution genomic microarrays commonly used as clinical assays. The combined detection of point mutations, indels and CNVs makes WES a very attractive first tier diagnostic test for genetically heterogeneous disorders. This article is protected by copyright. All rights reserved.
    Human Mutation 10/2013; 34(10). DOI:10.1002/humu.22387 · 5.05 Impact Factor
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