@article {358, title = {Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {613-617}, abstract = {

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

}, keywords = {Abnormalities, Multiple, Animals, Bone Diseases, Developmental, Cell Line, Chromosome Disorders, Craniofacial Abnormalities, Feeding and Eating Disorders, Female, Fusion Proteins, bcr-abl, Germ-Line Mutation, Heart Defects, Congenital, HEK293 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Limb Deformities, Congenital, Male, Mice, Mice, Knockout, Philadelphia Chromosome, Phosphorylation, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3815}, author = {Wang, Xia and Charng, Wu-Lin and Chen, Chun-An and Rosenfeld, Jill A and Al Shamsi, Aisha and Al-Gazali, Lihadh and McGuire, Marianne and Mew, Nicholas Ah and Arnold, Georgianne L and Qu, Chunjing and Ding, Yan and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Plon, Sharon E and Lupski, James R and Schaaf, Christian P and Yang, Yaping} } @article {357, title = {Lessons learned from additional research analyses of unsolved clinical exome cases.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 03 21}, pages = {26}, abstract = {

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36\% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51\% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6\%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6\%), 1/1 multiplex family involving three affected siblings, and 3/4 (75\%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

}, keywords = {Adenosine Triphosphatases, ATPases Associated with Diverse Cellular Activities, Computational Biology, DNA Copy Number Variations, DNA-Binding Proteins, Exome, Female, Genetic Diseases, Inborn, Genomics, GTP-Binding Protein beta Subunits, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mitochondrial Proteins, Pilot Projects, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcription Factors}, issn = {1756-994X}, doi = {10.1186/s13073-017-0412-6}, author = {Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Harel, Tamar and Rosenfeld, Jill A and Gambin, Tomasz and Stray-Pedersen, Asbj{\o}rg and K{\"u}ry, S{\'e}bastien and Mercier, Sandra and Lessel, Davor and Denecke, Jonas and Wiszniewski, Wojciech and Penney, Samantha and Liu, Pengfei and Bi, Weimin and Lalani, Seema R and Schaaf, Christian P and Wangler, Michael F and Bacino, Carlos A and Lewis, Richard Alan and Potocki, Lorraine and Graham, Brett H and Belmont, John W and Scaglia, Fernando and Orange, Jordan S and Jhangiani, Shalini N and Chiang, Theodore and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Xia, Fan and Beaudet, Arthur L and Boerwinkle, Eric and Eng, Christine M and Plon, Sharon E and Sutton, V Reid and Gibbs, Richard A and Posey, Jennifer E and Yang, Yaping and Lupski, James R} } @article {339, title = {Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 01 05}, pages = {21-31}, abstract = {

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2\%); among these patients, 101 (4.9\%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8\% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7\% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7\% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9\%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77{\texttimes}10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9\% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

}, keywords = {Exome, Genetic Diseases, Inborn, Genetic Variation, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Phenotype, Retrospective Studies, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa1516767}, author = {Posey, Jennifer E and Harel, Tamar and Liu, Pengfei and Rosenfeld, Jill A and James, Regis A and Coban Akdemir, Zeynep H and Walkiewicz, Magdalena and Bi, Weimin and Xiao, Rui and Ding, Yan and Xia, Fan and Beaudet, Arthur L and Muzny, Donna M and Gibbs, Richard A and Boerwinkle, Eric and Eng, Christine M and Sutton, V Reid and Shaw, Chad A and Plon, Sharon E and Yang, Yaping and Lupski, James R} } @article {540, title = {Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 12 04}, pages = {e173438}, abstract = {

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children{\textquoteright}s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7\%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0\%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8\%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9\%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1\%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

}, keywords = {Adult, Critical Care, Disease Management, Exome, Genetic Counseling, Genetic Diseases, Inborn, Humans, Infant, Infant Care, Infant, Newborn, Intensive Care Units, Pediatric, Length of Stay, Retrospective Studies, Texas, Whole Exome Sequencing}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.3438}, author = {Meng, Linyan and Pammi, Mohan and Saronwala, Anirudh and Magoulas, Pilar and Ghazi, Andrew Ray and Vetrini, Francesco and Zhang, Jing and He, Weimin and Dharmadhikari, Avinash V and Qu, Chunjing and Ward, Patricia and Braxton, Alicia and Narayanan, Swetha and Ge, Xiaoyan and Tokita, Mari J and Santiago-Sim, Teresa and Dai, Hongzheng and Chiang, Theodore and Smith, Hadley and Azamian, Mahshid S and Robak, Laurie and Bostwick, Bret L and Schaaf, Christian P and Potocki, Lorraine and Scaglia, Fernando and Bacino, Carlos A and Hanchard, Neil A and Wangler, Michael F and Scott, Daryl and Brown, Chester and Hu, Jianhong and Belmont, John W and Burrage, Lindsay C and Graham, Brett H and Sutton, Vernon Reid and Craigen, William J and Plon, Sharon E and Lupski, James R and Beaudet, Arthur L and Gibbs, Richard A and Muzny, Donna M and Miller, Marcus J and Wang, Xia and Leduc, Magalie S and Xiao, Rui and Liu, Pengfei and Shaw, Chad and Walkiewicz, Magdalena and Bi, Weimin and Xia, Fan and Lee, Brendan and Eng, Christine M and Yang, Yaping and Lalani, Seema R} } @article {110, title = {Molecular diagnostic experience of whole-exome sequencing in adult patients.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 07}, pages = {678-85}, abstract = {

PURPOSE: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.

METHODS: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.

RESULTS: Molecular diagnoses were reported for 17.5\% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2\%; P = 0.0003); the diagnostic rate was higher (23.9\%) for those 18-30 years of age compared to patients older than 30 years (10.4\%; P = 0.0001). Dual Mendelian diagnoses contributed to 7\% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4\% of autosomal dominant diagnoses.

CONCLUSION: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.

}, keywords = {Adult, Exome, Female, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Genetic Testing, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Pathology, Molecular}, issn = {1530-0366}, doi = {10.1038/gim.2015.142}, author = {Posey, Jennifer E and Rosenfeld, Jill A and James, Regis A and Bainbridge, Matthew and Niu, Zhiyv and Wang, Xia and Dhar, Shweta and Wiszniewski, Wojciech and Akdemir, Zeynep H C and Gambin, Tomasz and Xia, Fan and Person, Richard E and Walkiewicz, Magdalena and Shaw, Chad A and Sutton, V Reid and Beaudet, Arthur L and Muzny, Donna and Eng, Christine M and Yang, Yaping and Gibbs, Richard A and Lupski, James R and Boerwinkle, Eric and Plon, Sharon E} } @article {81, title = {Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Feb 18}, pages = {10713}, abstract = {

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

}, keywords = {ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters, Bile Acids and Salts, Cholestasis, Intrahepatic, Female, Humans, Male, Mutation, Receptors, Cytoplasmic and Nuclear, Young Adult}, issn = {2041-1723}, doi = {10.1038/ncomms10713}, author = {Gomez-Ospina, Natalia and Potter, Carol J and Xiao, Rui and Manickam, Kandamurugu and Kim, Mi-Sun and Kim, Kang Ho and Shneider, Benjamin L and Picarsic, Jennifer L and Jacobson, Theodora A and Zhang, Jing and He, Weimin and Liu, Pengfei and Knisely, A S and Finegold, Milton J and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M and Yang, Yaping and Washington, Gabriel C and Porteus, Matthew H and Berquist, William E and Kambham, Neeraja and Singh, Ravinder J and Xia, Fan and Enns, Gregory M and Moore, David D} } @article {248, title = {De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {784-9}, abstract = {

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25\% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

}, keywords = {Child, Child, Preschool, DNA-Binding Proteins, Exome, Female, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Muscle Hypotonia, Mutation, Sleep Apnea Syndromes, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.006}, author = {Xia, Fan and Bainbridge, Matthew N and Tan, Tiong Yang and Wangler, Michael F and Scheuerle, Angela E and Zackai, Elaine H and Harr, Margaret H and Sutton, V Reid and Nalam, Roopa L and Zhu, Wenmiao and Nash, Margot and Ryan, Monique M and Yaplito-Lee, Joy and Hunter, Jill V and Deardorff, Matthew A and Penney, Samantha J and Beaudet, Arthur L and Plon, Sharon E and Boerwinkle, Eric A and Lupski, James R and Eng, Christine M and Muzny, Donna M and Yang, Yaping and Gibbs, Richard A} } @article {217, title = {Molecular findings among patients referred for clinical whole-exome sequencing.}, journal = {JAMA}, volume = {312}, year = {2014}, month = {2014 Nov 12}, pages = {1870-9}, abstract = {

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient{\textquoteright}s physician. The patients were primarily pediatric (1756 [88\%]; mean age, 6 years; 888 females [44\%], 1101 males [55\%], and 11 fetuses [1\% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2\%) with 58\% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2\%; 95\% CI, 23.5\%-31.2\%) for the neurological group, 282/1147 (24.6\%; 95\% CI, 22.1\%-27.2\%) for the neurological plus other organ systems group, 30/83 (36.1\%; 95\% CI, 26.1\%-47.5\%) for the specific neurological group, and 49/244 (20.1\%; 95\% CI, 15.6\%-25.8\%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1\%) autosomal dominant, 181 (34.3\%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3\%) X-linked, and 1 (0.2\%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6\%) had blended phenotypes resulting from 2 single gene defects. About 30\% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6\%), including 59 patients (3\%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25\% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Fetus, Genetic Diseases, Inborn, Genetic Testing, Genomics, Humans, Incidental Findings, Infant, Infant, Newborn, Male, Molecular Diagnostic Techniques, Mutation, Phenotype, Referral and Consultation, Sequence Analysis, DNA}, issn = {1538-3598}, doi = {10.1001/jama.2014.14601}, author = {Yang, Yaping and Muzny, Donna M and Xia, Fan and Niu, Zhiyv and Person, Richard and Ding, Yan and Ward, Patricia and Braxton, Alicia and Wang, Min and Buhay, Christian and Veeraraghavan, Narayanan and Hawes, Alicia and Chiang, Theodore and Leduc, Magalie and Beuten, Joke and Zhang, Jing and He, Weimin and Scull, Jennifer and Willis, Alecia and Landsverk, Megan and Craigen, William J and Bekheirnia, Mir Reza and Stray-Pedersen, Asbjorg and Liu, Pengfei and Wen, Shu and Alcaraz, Wendy and Cui, Hong and Walkiewicz, Magdalena and Reid, Jeffrey and Bainbridge, Matthew and Patel, Ankita and Boerwinkle, Eric and Beaudet, Arthur L and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M} } @article {323, title = {Incidental copy-number variants identified by routine genome testing in a clinical population.}, journal = {Genet Med}, volume = {15}, year = {2013}, month = {2013 Jan}, pages = {45-54}, abstract = {

PURPOSE: Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained.

METHODS: Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed.

RESULTS: In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients{\textquoteright} referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition.

CONCLUSION: Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient.

}, keywords = {Age of Onset, Base Sequence, Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Order, Genetic Predisposition to Disease, Humans, Inheritance Patterns, Male, Reproducibility of Results}, issn = {1530-0366}, doi = {10.1038/gim.2012.95}, author = {Boone, Philip M and Soens, Zachry T and Campbell, Ian M and Stankiewicz, Pawel and Cheung, Sau Wai and Patel, Ankita and Beaudet, Arthur L and Plon, Sharon E and Shaw, Chad A and McGuire, Amy L and Lupski, James R} }