Abstract
Genomic technologies, such as whole-exome sequencing, are a powerful tool in genetic research. Such testing yields a great deal of incidental medical information, or medical information not related to the primary research target. We describe the management of incidental medical information derived from whole-exome sequencing in the research context. We performed whole-exome sequencing on a monozygotic twin pair in which only 1 child was affected with congenital anomalies and applied an institutional review board–approved algorithm to determine what genetic information would be returned. Whole-exome sequencing identified 79 525 genetic variants in the twins. Here, we focus on novel variants. After filtering artifacts and excluding known single nucleotide polymorphisms and variants not predicted to be pathogenic, the twins had 32 novel variants in 32 genes that were felt to be likely to be associated with human disease. Eighteen of these novel variants were associated with recessive disease and 18 were associated with dominantly manifesting conditions (variants in some genes were potentially associated with both recessive and dominant conditions), but only 1 variant ultimately met our institutional review board–approved criteria for return of information to the research participants.
KEY WORDS: whole-exome sequencing, incidental medical information
The advent of “Next Generation” sequencing technologies has allowed large-scale genomic sequencing to become widely used in genetic research. One type of genomic analysis, whole-exome sequencing, refers to the sequencing of the exome, or all the known coding regions (∼1%) of the genome.1 This technology is an efficient, affordable, and powerful research tool.1–6 Genomic sequencing necessarily reveals incidental medical information, or medical information that has potential health or reproductive importance, but is not related to the primary research question.1,7–9 Managing this incidental medical information presents many logistical and ethical challenges, especially as relates to novel variants.10,11 Guidelines have been proposed to help guide the return of incidental genetic information, but it can be difficult to conceptualize the ramifications of a given algorithm in the abstract.12–14 Here, we illustrate the incidental information revealed by whole-exome sequencing and provide an example of the decision process by which novel variants were determined to meet criteria for return to participants.
Patient Presentation
Through our National Human Genome Research Institute institutional review board (IRB)-approved protocol on VACTERL (vertebral defects–anal atresia–cardiovascular anomalies–tracheoesophageal fistula with esophageal atresia–radial and renal dysplasia–limb defects) association, which uses whole-exome sequencing (among other research modalities), we studied a monozygotic twin-pair in which only 1 twin was affected, with appropriate consent obtained from all participants, and with a separate consent required to perform genomic sequencing. Potential incidental medical information is discussed in detail during the consent process, and research participants choose whether to learn the results of genomic sequencing, both regarding the primary research target, as well as related to incidental medical information.
We extracted DNA from peripheral blood samples. Confirmation of mutations that met criteria for return was undertaken through Clinical Laboratory Improvement Amendment, 1988 (CLIA)-approved laboratories, either through DNA extracted from lymphoblastoid cell lines, or from a new blood sample. For specific genes for which CLIA testing is not available, we use commercial laboratories that are able to perform CLIA-based confirmation of any genetic variant identified through research laboratories (we perform confirmation through GeneDx, Gaithersburg, MD). Of note, some research laboratories also have their own, noncommercial CLIA laboratories that are able to perform CLIA verification on any genetic variant.
See Supplemental Information for detailed whole-exome sequencing and analysis methods. After variant analysis, the data were initially filtered to eliminate likely false-positives; genotypes were called at all positions with high-quality sequence bases (Phred-like Q20 or greater) by using a Bayesian algorithm (Most Probable Genotype [MPG]).15 Genotypes with MPG score ≥10 demonstrate >99.89% concordance with high-density single-nucleotide polymorphism (SNP) array data, and were considered high quality if they also had an MPG score/coverage ratio of ≥0.5. Variants predicted not to result in potential pathogenicity were excluded (based on Conserved Domain-based Prediction scores that predict pathogenicity; see http://research.nhgri.nih.gov/software/VarSifter for details). High-quality predicted pathogenic variants were analyzed by using standard available databases, including the Human Genome Mutation Database (professional version) (http://www.hgmd.cf.ac.uk/ac/index.php) and Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim), and through literature review. Further comparison of variants of interest was performed versus results of whole-exome sequencing of 479 whole-exome samples (sequenced at the same sequencing facility) ascertained from the ClinSeq cohort, which ascertains patients with a phenotypic continuum from unaffected, to those who have had myocardial infarctions.16 A working committee consisting of board-certified clinical geneticists, board-certified molecular geneticists, board-certified genetic counselors, bioethicists, and National Human Genome Research Institute IRB members, as well as other genetic researchers, convened to discuss variants that met the above criteria. Finally, in several cases, experts in the study of individual genes and conditions were contacted when results remained equivocal. IRB-approved guidelines regarding what incidental medical information would be returned to study participants are summarized as follows:
The genetic change must be known or predicted to be of urgent clinical significance.
Knowledge of the finding must have a clear direct benefit that would be lost if diagnosis was made later; that is, knowledge of this risk factor would substantially alter medical or reproductive decision-making.
The potential benefit of knowing a genetic disorder exists clearly outweighs the potential risks of anxiety and subsequent medical testing that could result from this knowledge.
Unless they add substantial risk, risk factors for multifactorial disorders are not reported.
Recessive mutations will be reported only if (1) the carrier frequency for mutations in that specific gene is >1% (such that the disease incidence is more than 1/40 000); (2) the syndrome results in significant morbidity; or (3) early diagnosis and intervention would have significant benefit.
Monozygosity was initially confirmed by high-density SNP microarray. Whole-exome sequencing did not reveal an obvious genetic cause of the congenital anomalies in the affected twin, although studies are ongoing regarding several variants of interest. High-quality genotypes were 98.9% concordant in the twins; see Table 1 for details of overall sequencing results. After eliminating known SNPs not meeting criteria outlined above and likely nonpathogenic variants, as well as artifacts (both by examining MPG and coverage data from next-generation sequencing, as well as by comparison with 479 other whole-exome samples), a total of 412 variants were identified. Of these, 32 novel variants (25 missense and 7 insertion-deletions) in 30 genes were felt to be likely associated with human disease (Table 2). Eighteen variants were associated with recessive diseases (manifesting in the homozygous or compound heterozygous state), and 17 were associated with conditions for which the presence of a single mutation (heterozygosity) was associated with disease in a dominant model (variants in some genes were associated with both recessive and dominant conditions). Some of these dominant-model genes were associated with increased susceptibility to a complex condition, such as schizophrenia or inflammatory bowel disease, whereas others were related to more traditional Mendelian disorders, although there was no clinical evidence for these disorders in the participants or their families, indicating that the variant was nonpathogenic, nonpenetrant, or that the reported gene-disease association was spurious.
TABLE 1.
Overview of Variants Detected in the Monozygotic Twins Through Whole-Exome Sequencing
Total variantsa | 79 525 |
Total variants with high-quality genotypesb | Twin A: 62 504 |
Twin B: 64 926 | |
Total variants where there is a high-quality genotype available for both twins | 52 143 (98.9% concordance: 51 566 concordant variants; 577 discordant variants) |
Variants in dbSNP (build 130) | 43 300 |
Synonymous variants | 8428 |
Nonsynonymous variants | 7660 |
In-frame insertions/deletions | 77 |
Frameshift mutations | 68 |
Nonsense variants | 49 |
Splice-site mutations | 37 |
Differences from the human reference sequence, build National Center for Biotechnology Information 36.
Based on MPG score ≥10 and score/coverage ratio ≥0.5.
TABLE 2.
Identified Genes With Novel Variants Potentially Associated With Disease, Including Carrier States for Recessive Conditions
Number | Gene | Variant Type | Disease(s)a | Type of Association | Notes/Reason Information Not Returned | Reference(s) |
---|---|---|---|---|---|---|
1 | ABCC8 | M | Hyperinsulinemic hypoglycemia, permanent neonatal diabetes with neurologic features, transient and permanent neonatal diabetes mellitus | Disease-associated gene (dominant)a and/or carrier for recessive disorder | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 23–26 |
2 | AK2 | M | Reticular dysgenesis | Carrier for recessive disorder | Rare recessive disorder | 27 |
3 | CACNA1S | M | Malignant hyperthermia, hypokalemic periodic paralysis | Susceptibility for conditions and/or disease-associated gene (dominant) | The specific variant in this family was ultimately not felt to be pathogenic per discussion with multiple experts in the conditions studied | 17,18 |
4 | CD320 | DIV | Methylmalonic aciduria (owing to transcobalamin receptor defect) | Carrier for recessive disorder | Rare recessive disorder | 28 |
5 | CISD2b | M | Wolfram syndrome | Carrier for recessive disorder | Rare recessive disorder | 29 |
6 | COL5A2 | M | Ehlers-Danlos syndrome type I | Disease-associated gene (dominant) | The individuals and their family do not meet criteria for diagnosis, but preliminary evidence suggests that this variant may be related to the congenital anomaly that is the primary focus of this research | 30 |
7 | COL6A3 | DIV | Bethlem myopathy, Ullrich congenital muscular dystrophy (autosomal recessive and dominant forms) | Disease-associated gene (dominant) and/or carrier for recessive disorder | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 31–33 |
8 | CPSI | M | Carbamoyl phosphate synthetase deficiency, pulmonary artery hypertension | Carrier for recessive disorder and possibly related to susceptibility to conditions | Rare recessive disorder | 19–21 |
9 | CRYGD | M | Progressive juvenile-onset punctate cataracts | Disease-associated gene (dominant) | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 34 |
10 | CYP21A2 | DIV | Congenital adrenal hyperplasia | Carrier for recessive disorder | Normal variant in private databases of researchers studying this gene/condition | 22 |
11 | DBH | M | Dopamine β-hydroxylase deficiency, norepinephrine deficiency | Carrier for recessive disorders | Rare recessive disorder | 35–37 |
12 | DDX11 | M | Warsaw breakage syndrome | Carrier for recessive disorder | Rare recessive disorder | 38 |
13 | DISC1 | M | Possible association with schizophrenia | Possibly related to susceptibility for a condition | Susceptibility factor, not clear if this specific variant is associated with this condition in this family | 39–42 |
14 | DNAH5 | M | Primary ciliary dyskinesia type 3 | Carrier for recessive disorder | Primary ciliary dyskinesia is more common than 1/40 000, but only about 25% of cases are caused by mutations in DNAH5 | 43 |
15 | FOXD4b | M | Cardiomyopathy, obsessive-compulsive disorder, suicidality | Disease-associated gene (dominant) | Complex purported gene-associated phenotype reported in 1 family, susceptibility factor | 44 |
16 | FUT7 | M | Possible autosomal recessive association with multiple autoimmune conditions | Carrier for recessive disorder | Rare recessive disorder | 45 |
17 | GIGYF2 | DIV | Familial Parkinson’s disease (incompletely penetrant) | Possibly related to susceptibility for a condition | No signs in family, not clear if this specific variant is associated with this condition in this family | 46,47 |
18 | HMOX1 | M | Heme-oxygenase 1 deficiency | Carrier for recessive disorder and possibly related to susceptibility for a condition | Rare recessive disorder, possible association with COPD is a susceptibility factor | 48–50 |
19 | HSPG2 | M | Schwartz-Jampel syndrome type 1; dyssegmental dysplasia, Silverman-Handmaker type | Carrier for recessive disorders | Rare recessive disorder | 51 |
20 | KRT18 | M | Possible association with susceptibility to cirrhosis | Possibly related to susceptibility for a condition | Susceptibility factor | 52–55 |
21 | MST1 | M | Possible association with inflammatory bowel disease | Possibly related to susceptibility for a condition | Susceptibility factor | 56,57 |
22 | NLRP12 | M | Familial cold autoinflammatory syndrome | Disease-associated gene (dominant) | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 58 |
23 | ORAI1 | DIV | Immune dysfunction | Carrier for recessive disorder | Rare recessive disorder, although heterozygotes may have subtle subclinical manifestations | 59 |
24 | PRDM9 | M | Possible association with azoospermia | Possibly related to susceptibility for a condition | Susceptibility factor | 60, 61 |
25 | PRKCSH | DIV | Autosomal dominant polycystic liver disease | Disease-associated gene (dominant) | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 62 |
26 | PRKRA | M | Dystonia 16 | Carrier for recessive disorder | Generally viewed as a rare recessive disorder, although affected heterozygote reported (possibly related to compound heterozygosity or other explanation) | 63,64 |
27 | PSPHb | M | Phosphoserine phosphatase deficiency | Carrier for recessive disorder | Rare recessive disorder | 65 |
28 | SCARB2 | M | Action myoclonus-renal failure | Carrier for recessive disorder | Rare recessive disorder | 66 |
29 | SLC1A3 | DIV | Episodic ataxia, type 6 | Disease-associated gene (dominant) | No signs in participants or family, not clear if this specific variant is associated with this condition in this family | 67 |
30 | TH | M | Segawa syndrome | Carrier for recessive disorder | Rare recessive disorder | 68 |
31 | TRPC7 | M | Possible association with bipolar affective disorder, ALS, and Parkinsonism | Possibly related to susceptibility for conditions | Susceptibility factors, no family history of these conditions and not clear if this specific variant is associated with this condition in this family | 69,70 |
32 | USP26 | M | Possible association with impaired spermatogenesis | Possibly related to susceptibility for a condition | Susceptibility factors, not clear if this specific variant is associated with this condition in this family | 71–74 |
As known SNPs do meet criteria for return of information when associated with increased susceptibility for a genetic condition, these are not included here. ALS, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary disease; DIV, in-frame deletion or insertion variant; M, missense (nonsynonymous) variant.
“Disease-associated genes (dominant)” indicates that studies show that only 1 mutant gene is required for the presence of disease, as opposed to recessive conditions, in which carriers of a single mutation are classically considered to be unaffected.
Variants called in only 1 of the twins; however, in the twin in whom the variant was not called, the variant is likely present, as the coverage was low for that base in the twin without the variant.
Three heterozygous variants initially met criteria for return of information: CACNA1S, associated with hypokalemic periodic paralysis and malignant hyperthermia17,18; CPSI, associated with Carbamoyl Phosphate Synthetase I deficiency, as well as pulmonary artery hypertension,19–21 the latter of which this participant had; and CYP21A2, associated with 21-hydroxylase deficiency leading to congenital adrenal hyperplasia.22 Experts in each of the diseases/genes were contacted, as pathogenicity was not clear in all cases. Of these, after extensive discussion, it was unclear (but felt to be unlikely) whether the specific variant identified in CACNA1S was pathogenic, and because the research participants and their relatives showed no signs of these CACNA1S-related conditions, it was determined that this result did not meet criteria for return. In discussion with individual researchers, strong evidence emerged that the variant in CYP21A2 was nonpathogenic through (private, unpublished) work of researchers specializing in this disease (Maria New, MD; Tony Yuen, PhD). There was evidence that the CPSI mutation was pathogenic as relates to postoperative pulmonary artery hypertension, which the affected twin suffered, and, as there is a potential intervention (special anesthesiology considerations in future surgeries), this was deemed to meet requirements for return to the participants.
Discussion
New technologies allow researchers to examine large portions of the genome with relative ease. These are valuable tools, and reveal a large amount of potentially medically significant information that, with in-depth analysis, can be used to facilitate health care8,9; however, the presence of incidental medical information may also impede the use of genomic sequencing. Challenges directly related to incidental genomic information in clinical practice involve complex and resource-consuming interpretation and validation of data, the possibility of subjecting patients to risky and unnecessary follow-up testing, and questions about the overall risk-benefit ratio of conducting such testing.11 In the research setting, similar issues also apply, and hinge on specific IRB-approved guidelines.
One central issue in the research context involves defining and determining what genetic information should be returned to research participants who undergo this type of sequencing. In our experience, and in discussions with a number of other researchers using these sequencing methods, there is a wide range of opinions. These opinions range from returning no incidental medical information (because of logistical concerns as well as the argument that that the overall risk would outweigh the benefits), to returning large amounts of information involving personal and familial genetic risk factors for disease, to returning all genetic data in an uncurated fashion so that research participants and their physicians can access this information prospectively. Likewise, although there is no single accepted algorithm in the medical literature, various criteria have been proposed regarding which information should be returned. Unifying themes of these recommendations involve the following: allowing research participants to choose whether they want to learn about incidental medical information; the need for filtering and confirmation of variants owing to the inevitable false-positive variant calls; the requirement to show that the findings are valid in terms of pathogenicity, which can be far more demanding; and requirements that the returned genetic information involves a relatively high risk for disease, that the information is actionable, and that the benefits of knowing the genetic information outweigh the risks.7,11,13 Other recommendations focus on specific context, taking into account the nature of the variant, the parameters of the research study, and the characteristics of the research participants.12,14
Despite optimal guidance and careful algorithms, there will inevitably be variants that fall into “gray zones” in the decision-making process. For such variants, we use a multidisciplinary approach drawing on experts from multiple fields, but this can be a laborious process that draws resources away from direct research goals. This report demonstrates that a large amount of effort was required to return only 1 incidental genomic variant found through whole-exome sequencing. One proposal to help manage the workload in a streamlined manner is to establish collective groups experienced in interpretation of genomic sequencing to automate the process of both analyzing research results, as well as aiding in interpretation, validation, and return of results.
Supplementary Material
Acknowledgment
The authors are extremely grateful to Dr Leslie G. Biesecker (Chief and Senior Investigator, Genetic Disease Research Branch, National Human Genome Research Institute) for access to large-scale sequencing data for use as comparison samples.
Glossary
- CLIA
Clinical Laboratory Improvement Amendment, 1988;
- IRB
institutional review board
- MPG
Most Probable Genotype
- SNP
single-nucleotide polymorphism
Footnotes
All authors have made substantive intellectual contributions to this study. All authors have made substantial contributions in each of the following categories: (1) conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services. Funded by the National Institutes of Health (NIH).
References
- 1.Tucker T, Marra M, Friedman JM. Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet. 2009;85(2):142–154 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010;19(R2):R145–R151 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42(1):30–35 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Roach JC, Glusman G, Smit AF, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010;328(5978):636–639 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790–793 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ng SB, Nickerson DA, Bamshad MJ, Shendure J. Massively parallel sequencing and rare disease. Hum Mol Genet. 2010;19(R2):R119–R124 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wolf SM, Lawrenz FP, Nelson CA, et al. Managing incidental findings in human subjects research: analysis and recommendations. J Law Med Ethics 2008;36(2):219–248, 211 [DOI] [PMC free article] [PubMed]
- 8.Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362(13):1181–1191 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375(9725):1525–1535 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.McGuire AL, Lupski JR. Personal genome research: what should the participant be told? Trends Genet. 2010;26(5):199–201 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kohane IS, Masys DR, Altman RB. The incidentalome: a threat to genomic medicine. JAMA. 2006;296(2):212–215 [DOI] [PubMed] [Google Scholar]
- 12.Ravitsky V, Wilfond BS. Disclosing individual genetic results to research participants. Am J Bioeth. 2006;6(6):8–17 [DOI] [PubMed] [Google Scholar]
- 13.Fabsitz RR, McGuire A, Sharp RR, et al. National Heart, Lung, and Blood Institute working group Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ Cardiovasc Genet. 2010;3(6):574–580 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Beskow LM, Burke W. Offering individual genetic research results: context matters. Sci Transl Med 2010;2(38):38cm20 [DOI] [PMC free article] [PubMed]
- 15.Teer JK, Bonnycastle LL, Chines PS, et al. NISC Comparative Sequencing Program Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res. 2010;20(10):1420–1431 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Biesecker LG, Mullikin JC, Facio FM, et al. NISC Comparative Sequencing Program The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res. 2009;19(9):1665–1674 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Jurkat-Rott K, Lehmann-Horn F, Elbaz A, et al. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet. 1994;3(8):1415–1419 [DOI] [PubMed] [Google Scholar]
- 18.Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997;60(6):1316–1325 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Hoshide R, Matsuura T, Haraguchi Y, Endo F, Yoshinaga M, Matsuda I. Carbamyl phosphate synthetase I deficiency. One base substitution in an exon of the CPS I gene causes a 9-basepair deletion due to aberrant splicing. J Clin Invest. 1993;91(5):1884–1887 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension—urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001;344(24):1832–1838 [DOI] [PubMed] [Google Scholar]
- 21.Summar ML, Gainer JV, Pretorius M, et al. Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension. 2004;43(2):186–191 [DOI] [PubMed] [Google Scholar]
- 22.White PC, Chaplin DD, Weis JH, Dupont B, New MI, Seidman JG. Two steroid 21-hydroxylase genes are located in the murine S region. Nature 1984;5;312(5993):465–467 [DOI] [PubMed]
- 23.Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995;268(5209):426–429 [DOI] [PubMed] [Google Scholar]
- 24.Babenko AP, Polak M, Cavé H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355(5):456–466 [DOI] [PubMed] [Google Scholar]
- 25.Proks P, Arnold AL, Bruining J, et al. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet. 2006;15(11):1793–1800 [DOI] [PubMed] [Google Scholar]
- 26.Ellard S, Flanagan SE, Girard CA, et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet. 2007;81(2):375–382 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Pannicke U, Hönig M, Hess I, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet. 2009;41(1):101–105 [DOI] [PubMed] [Google Scholar]
- 28.Quadros EV, Lai SC, Nakayama Y, et al. Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). Hum Mutat. 2010;31(8):924–929 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Amr S, Heisey C, Zhang M, et al. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet. 2007;81(4):673–683 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Michalickova K, Susic M, Willing MC, Wenstrup RJ, Cole WG. Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce Ehlers-Danlos syndrome type I. Hum Mol Genet. 1998;7(2):249–255 [DOI] [PubMed] [Google Scholar]
- 31.Pan TC, Zhang RZ, Pericak-Vance MA, et al. Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum Mol Genet. 1998;7(5):807–812 [DOI] [PubMed] [Google Scholar]
- 32.Demir E, Sabatelli P, Allamand V, et al. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet. 2002;70(6):1446–1458 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Baker NL, Mörgelin M, Peat R, et al. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet. 2005;14(2):279–293 [DOI] [PubMed] [Google Scholar]
- 34.Stephan DA, Gillanders E, Vanderveen D, et al. Progressive juvenile-onset punctate cataracts caused by mutation of the gammaD-crystallin gene. Proc Natl Acad Sci U S A. 1999;96(3):1008–1012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.McKinney EF, Walton RT, Yudkin P, et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics. 2000;10(6):483–491 [DOI] [PubMed] [Google Scholar]
- 36.Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR. Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine. Neurogenetics. 2000;3(1):35–40 [DOI] [PubMed] [Google Scholar]
- 37.Kim CH, Zabetian CP, Cubells JF, et al. Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet. 2002;108(2):140–147 [PubMed] [Google Scholar]
- 38.van der Lelij P, Chrzanowska KH, Godthelp BC, et al. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet. 2010;86(2):262–266 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000;9(9):1415–1423 [DOI] [PubMed] [Google Scholar]
- 40.Ekelund J, Hovatta I, Parker A, et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet. 2001;10(15):1611–1617 [DOI] [PubMed] [Google Scholar]
- 41.Song W, Li W, Feng J, Heston LL, Scaringe WA, Sommer SS. Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochem Biophys Res Commun. 2008;367(3):700–706 [DOI] [PubMed] [Google Scholar]
- 42.Schumacher J, Laje G, Abou Jamra R, et al. The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations. Hum Mol Genet. 2009;18(14):2719–2727 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Olbrich H, Häffner K, Kispert A, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002;30(2):143–144 [DOI] [PubMed] [Google Scholar]
- 44.Minoretti P, Arra M, Emanuele E, et al. A W148R mutation in the human FOXD4 gene segregating with dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality. Int J Mol Med. 2007;19(3):369–372 [PubMed] [Google Scholar]
- 45.Bengtson P, Larson C, Lundblad A, Larson G, Påhlsson P. Identification of a missense mutation (G329A;Arg(110)—> GLN) in the human FUT7 gene. J Biol Chem. 2001;276(34):31575–31582 [DOI] [PubMed] [Google Scholar]
- 46.Lautier C, Goldwurm S, Dürr A, et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet. 2008;82(4):822–833 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Tan EK, Lin CH, Tai CH, et al. Non-synonymous GIGYF2 variants in Parkinson’s disease from two Asian populations. Hum Genet. 2009;126(3):425–430 [DOI] [PubMed] [Google Scholar]
- 48.Yachie A, Niida Y, Wada T, et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103(1):129–135 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Yamada N, Yamaya M, Okinaga S, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet. 2000;66(1):187–195 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Guénégou A, Leynaert B, Bénessiano J, et al. Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France. J Med Genet. 2006;43(8):e43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Nicole S, Davoine CS, Topaloglu H, et al. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet. 2000;26(4):480–483 [DOI] [PubMed] [Google Scholar]
- 52.Arikawa-Hirasawa E, Wilcox WR, Le AH, et al. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat Genet. 2001;27(4):431–434 [DOI] [PubMed] [Google Scholar]
- 53.Ku NO, Wright TL, Terrault NA, Gish R, Omary MB. Mutation of human keratin 18 in association with cryptogenic cirrhosis. J Clin Invest. 1997;99(1):19–23 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Ku NO, Darling JM, Krams SM, et al. Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies. Proc Natl Acad Sci U S A. 2003;100(10):6063–6068 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Strnad P, Zhou Q, Hanada S, et al; Acute Liver Failure Study Group. Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations. Gastroenterology 2010;139(3):828–835, 835.e1-3 [DOI] [PMC free article] [PubMed]
- 56.McGovern DP, Gardet A, Törkvist L, et al. NIDDK IBD Genetics Consortium Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010;42(4):332–337 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Tong P, Prendergast JG, Lohan AJ, et al. Sequencing and analysis of an Irish human genome. Genome Biol. 2010;11(9):R91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Jéru I, Duquesnoy P, Fernandes-Alnemri T, et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008;105(5):1614–1619 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Feske S, Gwack Y, Prakriya M, et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006;441(7090):179–185 [DOI] [PubMed] [Google Scholar]
- 60.Irie S, Tsujimura A, Miyagawa Y, et al. Single-nucleotide polymorphisms of the PRDM9 (MEISETZ) gene in patients with nonobstructive azoospermia. J Androl. 2009;30(4):426–431 [DOI] [PubMed] [Google Scholar]
- 61.Miyamoto T, Koh E, Sakugawa N, et al. Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest. J Assist Reprod Genet. 2008;25(11-12):553–557 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Drenth JP, te Morsche RH, Smink R, Bonifacino JS, Jansen JB. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat Genet. 2003;33(3):345–347 [DOI] [PubMed] [Google Scholar]
- 63.Camargos S, Scholz S, Simón-Sánchez J, et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 2008;7(3):207–215 [DOI] [PubMed] [Google Scholar]
- 64.Seibler P, Djarmati A, Langpap B, et al. A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient. Lancet Neurol. 2008;7(5):380–381 [DOI] [PubMed] [Google Scholar]
- 65.Veiga-da-Cunha M, Collet JF, Prieur B, et al. Mutations responsible for 3-phosphoserine phosphatase deficiency. Eur J Hum Genet. 2004;12(2):163–166 [DOI] [PubMed] [Google Scholar]
- 66.Berkovic SF, Dibbens LM, Oshlack A, et al. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet. 2008;82(3):673–684 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65(4):529–534 [DOI] [PubMed] [Google Scholar]
- 68.Lüdecke B, Dworniczak B, Bartholomé K. A point mutation in the tyrosine hydroxylase gene associated with Segawa’s syndrome. Hum Genet. 1995;95(1):123–125 [DOI] [PubMed] [Google Scholar]
- 69.McQuillin A, Bass NJ, Kalsi G, et al. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Mol Psychiatry. 2006;11(2):134–142 [DOI] [PubMed] [Google Scholar]
- 70.Hermosura MC, Cui AM, Go RC, et al. Altered functional properties of a TRPM2 variant in Guamanian ALS and PD. Proc Natl Acad Sci U S A. 2008;105(46):18029–18034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. Possible role of USP26 in patients with severely impaired spermatogenesis. Eur J Hum Genet. 2005;13(3):336–340 [DOI] [PubMed] [Google Scholar]
- 72.Paduch DA, Mielnik A, Schlegel PN. Novel mutations in testis-specific ubiquitin protease 26 gene may cause male infertility and hypogonadism. Reprod Biomed Online. 2005;10(6):747–754 [DOI] [PubMed] [Google Scholar]
- 73.Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. Alterations of the USP26 gene in Caucasian men. Int J Androl. 2006;29(6):614–617 [DOI] [PubMed] [Google Scholar]
- 74.Zhang J, Qiu SD, Li SB, et al. Novel mutations in ubiquitin-specific protease 26 gene might cause spermatogenesis impairment and male infertility. Asian J Androl. 2007;9(6):809–814 [DOI] [PubMed] [Google Scholar]
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