Exon-Targeted Array CGH for Identification of Clinically Relevant Small-Sized, Intragenic CNVs

Ankita Patel , Jill Rosenfeld-Mokry , Tomasz Gambin , Pengfei Liu , Weimin Bi , Amy Breman , Janice Smith , Seema Lalani , Carlos Bacino , Art L. Beaudet , James R. Lupski , Chad A Shaw , Sau-Wai Cheung , P. Stankiewicz


Advances in genetic diagnostic technologies has allowed for monumental improvements in the diagnosis of genetic diseases. With newer technologies, offering improved diagnostic results, unexpected findings have also been delineated in some cases. Many groups have addressed this issue by providing guidelines delineating what results should be shared with patients. However, most of the guidelines and scientific thought has involved the study of pediatric patients and have addressed results from sequencing studies. We utilized results of 30,000 prenatal arrays and 6500 oncology arrays to provide information concerning the occurrence and importance of incidental findings in array studies in both of these populations. This experience has allowed us to formulate a protocol regarding how to proceed if an incidental result was encountered, and to postulate what should be reported back to patients.

The incidental findings seen in prenatal and oncology studies were detected at much different frequencies and have presented different challenges. In prenatal studies, incidental findings are detected in less than 0.1% of the patients and can placed into three, relatively equal occurring groups; (1) Adult disorders with minimal consequences (e.g. HNPP, CMT1A); (2) Adult/cancer disorders with serious consequences (e.g. BRCA1, MLH1); (3) Partial duplications of genes mentioned in above group (e.g. BRCA1, MLH1), but with no clear understanding of the effect of the partial duplication. All of these are reported to patients, however the counseling involved with the latter two is much more intensive.

In contrast to prenatal arrays, incidental findings in oncology arrays are much more frequent. In oncology studies, incidental findings are detected in less than ~2.5% of the patients and can be placed into seven groups, two which are much more frequent: (1) Microdeletion/duplications with variable expressivity and low penetrance that also may be seen in normal carriers (e.g. 16p13.11, 1q21.1, 17q12, 16p11.2, etc.) are reported back to the referring physicians with detailed information concerning the syndromes; (2) Microdeletion/duplications not considered to have a clinical effect or have a very low penetrance (e.g. CHRN7 duplication) are not reported out; (3) About ~10% of incidental findings are sex chromosome aberrations, similar to what have been previously reported in standard cytogenetic analysis (e.g. 47,XXY); (4) Adult disorders with more minimal consequences (e.g. HNPP, CMT1A) were infrequently seen (~2.4%); (5) In an equally small frequency specific genetic syndromes unrelated to the hematological findings were detected (e.g. Williams syndrome); (6) One of the most interesting findings concerned the delineation of genetic syndromes which may be connected to the hematological referrals of the patients, such as Joubert syndrome, VCF deletions and hemophilia; (7) Lastly 9 patients were detected with first or second degree consanguinity. This is at a much higher frequency than expected, and while this finding may be connected to an underlying recessive condition, this finding was not reported to patients.

Overall this work indicates that there are a variety of different types of incidental findings. These studies demonstrate that it is important to develop protocols for reporting the findings that facilitate appropriate medical follow-up in the necessary cases.

Author Ankita Patel
Ankita Patel,,
, Jill Rosenfeld-Mokry
Jill Rosenfeld-Mokry,,
, Tomasz Gambin II
Tomasz Gambin,,
- The Institute of Computer Science
, Pengfei Liu
Pengfei Liu,,
, Weimin Bi
Weimin Bi,,
, Amy Breman
Amy Breman,,
, Janice Smith
Janice Smith,,
, Seema Lalani
Seema Lalani,,
, Carlos Bacino
Carlos Bacino,,
, Art L. Beaudet
Art L. Beaudet,,
et al.
Journal seriesCancer Genetics, ISSN 2210-7762
Issue year2016
Publication size in sheets0.3
URL http://www.cancergeneticsjournal.org/article/S2210-7762(16)30133-8/fulltext
Languageen angielski
Score (nominal)25
ScoreMinisterial score = 25.0, 27-03-2017, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, 27-03-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.93 (2) - 2016=2.468 (5)
Citation count*0
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.