ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Expanded genetic screening panel for the Ashkenazi Jewish population Brett Baskovich, MD1, Susan Hiraki, MS, MPH2, Kinnari Upadhyay, MS2, Philip Meyer2, Shai Carmi, PhD3, Nir Barzilai, MD2, Ariel Darvasi, PhD4, Laurie Ozelius, PhD5, Inga Peter, PhD5, Judy H. Cho, MD5, Gil Atzmon, PhD2,6, Lorraine Clark, PhD7, Jin Yu, PhD8, Todd Lencz, PhD8, Itsik Pe’er, PhD9, Harry Ostrer, MD1,2, and Carole Oddoux, PhD1,2 Purpose: Carrier screening programs that identify the presence of American College of Medical Genetics and Genomics scoring known mutations have been effective for reducing the incidence of (ACMG) system. Other known mutations were identified through autosomal recessive conditions in the Ashkenazi Jewish (AJ) popu- literature review. lation and other populations. Yet, these programs have not realized Results: A panel of 163 mutations was identified for 76 autosomal their full potential. Furthermore, many known autosomal recessive recessive, 24 autosomal dominant, and 3 X-linked disorders. and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is Conclusion: Screening for a broader range of disorders not only unknown. could further reduce the incidence of autosomal recessive disorders Methods: Through literature review and annotation of full but also could offer the benefits of early or presymptomatic diagnosis. sequenced genomes from healthy individuals, we expanded the list Genet Med advance online publication 3 September 2015 of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical data- Key Words: Ashkenazi Jews; carrier screening; genetic testing; vari- bases and curated manually for clinical validity and utility using the ant annotation; whole genome sequencing INTRODUCTION prevalent in the Ashkenazi Jewish (AJ) population. Ethnicity- Population-based genetic screening is a valuable application of based carrier screening programs in this and other populations genomic technology that can have significant clinical and pub- have been successful in decreasing the incidence of autosomal lic health benefits. Presymptomatic detection of disease and recessive conditions.1 The best-known example is Tay-Sachs dis- identification of increased disease risk provide the opportunity ease, a severe, progressive neurodegenerative disorder caused for early diagnosis, intervention, or prevention. Identification by a defect in hexosaminidase A enzyme activity. Beginning of genetic carrier status provides the opportunity for reproduc- in 1970, Tay-Sachs carrier screening in AJ individuals was the tive counseling and family planning, allowing for the preven- first population-based public health initiative aimed at decreas- tion of the birth of an affected child or for early diagnosis and ing the incidence of a lethal genetic disease. This coordinated intervention.1 Many population-based screening programs tar- effort, which included education, genetic counseling, and vol- get specific populations, such as newborns, particular ethnic untary screening, was adopted throughout the United States as groups, or those deemed to be at increased risk for certain dis- well as internationally. Within 30 years of its inception, the pro- eases. With the advancement of genetic technologies, such as gram was successful in decreasing the incidence of Tay-Sachs multiplex testing to conduct high-throughput genotyping of a disease by more than 90% in the AJ populations of the United multitude of variants, there has been an expansion in the num- States and Canada.1 In addition to Tay-Sachs disease, there are ber of diseases that can be screened for in the predisposition, many other recessive disorders that occur more commonly in presymptomatic, and carrier states. Selecting conditions to the AJ population, and many laboratories now offer genetic include on a population-based screening panel and even select- carrier panels aimed at those of AJ ethnicity. The American ing the criteria to make this decision are still active questions. College of Medical Genetics and Genomics (ACMG) and the Founder effects, in combination with endogamy and pos- American College of Obstetricians and Gynecologists have set sible selection, have made some Mendelian conditions more forth recommendations for conditions that should be included B.B. is the first author. S.H. and K.U. are co-first authors. 1Department of Pathology, Montefiore Medical Center, New York, New York, USA; 2Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA; 3The Faculty of Medicine, Braun School of Public Health, Hebrew University of Jerusalem, Jerusalem, Israel; 4Department of Genetics, Hebrew University of Jerusalem, Givat Ram, Jerusalem; 5Department of Genetics, Icahn School of Medicine at Mount Sinai School of Medicine, New York, New York, USA; 6Faculty of Natural Science, University of Haifa, Haifa, Israel; 7Department of Pathology, Columbia University, New York, New York, USA; 8The Feinstein Institute for Medical Research, Manhasset, New York, USA; 9Department of Computer Science, Columbia University, New York, New York, USA. Correspondence: Harry Ostrer ([email protected]) Submitted 10 December 2014; accepted 22 July 2015; advance online publication 3 September 2015. doi:10.1038/gim.2015.123 522 Volume 18 | Number 5 | May 2016 | GeneticS in medicine Expanded Ashkenazi panel | BASKOVICH et al ORIGINAL RESEARCH ARTICLE on an AJ panel.2 Despite these recommendations, there are dif- studies (Supplementary Figure S1 online). A recent study that ferences between what is recommended and what is offered by performed whole-exome sequencing on 6,517 European and laboratories, as well as differences among the various labora- African Americans suggested that 45% of individuals carry at tories. In a multi-ethnic study of screening 23,000 individuals least one mutation in genes included on newborn screens.9 for 400+ Mendelian variants, including variants found among We recently sequenced 128 AJ individuals (The Ashkenazi AJ, this ethnic group was the most likely to have carriers of Genome Consortium data set, or “TAGC dataset”) and estab- serious recessive disorders. Many of these disorders were not lished a list of previously known and new mutations.10 Here we included on the ACMG or American College of Obstetricians address the pathogenicity of the newly identified mutations and and Gynecologists lists of recommendations.2 In addition, the the clinical utility of screening for them. AJ community has generally been supportive of carrier screen- ing for severe disorders and expansion beyond what is currently MATERIALS AND METHODS recommended. Therefore, expanding current AJ screening DNA samples were collected from 128 individuals who were panels to include more conditions appears justified. disease-free and were verified by principal component analysis In addition to carrier screening panels, there are a growing to have AJ origin, as we recently described.10 DNA sequenc- number of predisposition genetic screening panels that identify ing was performed by complete genomics (CG) and annotated those at increased risk for future disease. Currently, the targeted using the reference genome version hg19.10 population tends to be those already deemed to be at increased ClinVar and OMIM, publicly available genetic databases that risk due to their family history of disease. Cancer risk assess- catalog genotypes and phenotypes, were scanned via a custom ment represents an application of predisposition screening that web crawler to identify variants associated with phenotypes.11 provides the opportunity for prevention and early diagnosis to Of the 2,434 variants that were identified from sequencing 128 decrease risk.3 One such example is BRCA1/2 screening, which AJ individuals, 80 variants were reported by ClinVar or OMIM serves as a paradigm for high-risk, population-based screening. as “pathogenic” or “possibly pathogenic.” These variants were With an increasing number of disease risk variants being dis- curated manually by at least two independent reviewers through covered, genetic risk assessment for adult-onset conditions will literature review and assigned a score based on the ACMG scor- continue to grow.4 Some who might benefit from genetic risk ing system. An additional 56 variants were scored as “patho- assessment may escape attention due to incomplete penetrance, genic, very strong” using the ACMG system. Factors considered sex-limited expression, and lack of or limited personal and/ were number of patients, number of controls, association with or family history.5 Extending predisposition screening beyond other mutations, and functional studies (Supplementary those who meet standard high-risk criteria should have clinical Table S1 online).8 Those determined to be pathogenic or likely utility, especially when offered in multiplex format. pathogenic were further reviewed for individual clinical utility As the number of disease variants grows and technological and frequency of the variant and then confirmed for their pres- advances improve ease and efficiency of detection, criteria are ence in the AJ population using orthogonal whole genome (315 needed against which to judge the merits of adding new genetic subjects) or whole exome Illumina sequencing (640 subjects). tests. In 1968, Wilson and Jungner delineated the principles of Calculations