Limits...
A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility.

Perreault-Micale C, Davie J, Breton B, Hallam S, Greger V - Mol Genet Genomic Med (2015)

Bottom Line: Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity.The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay.All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria.

View Article: PubMed Central - PubMed

Affiliation: Good Start Genetics, Inc. 237 Putnam Avenue, Cambridge, Massachusetts, 02139.

ABSTRACT
Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic-specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay. The clinical utility of our approach was demonstrated by screening a pan-ethnic population of 22,864 individuals for Bloom syndrome carrier status using a BLM variant panel comprised of 50 pathogenic variants. In addition to carriers of the common AJ founder variant, we identified 57 carriers of other pathogenic BLM variants. All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria. Thus, it was possible to confidently report an increased number of Bloom's syndrome carriers compared to traditional, ethnicity-based screening, while not reducing the specificity of the screening due to reporting variants of unknown clinical significance.

No MeSH data available.


Related in: MedlinePlus

Ethnicity of the study population that included 22,864 individuals from fertility clinics within the United States.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4521971&req=5

fig02: Ethnicity of the study population that included 22,864 individuals from fertility clinics within the United States.

Mentions: 66% of patients reported ethnicity, country of origin, or a combination of both. We used the following ethnic categories: Asian, African-American, AJ, Caucasian (including French Canadian), Hispanic, other (all that did not fall into one of the above categories), and more than one ethnicity. 439 individuals reported AJ as their only ancestry. Since Bloom syndrome is considered to be an AJ disorder, 183 additional participants that reported AJ plus one or more other ethnicity were reassigned to the AJ group. The majority of them (147 individuals) identified themselves as AJ plus Caucasian or specified a country of origin indicative of Caucasian ancestry, such as Germany or Russia. The other 36 reported one or more other additional ethnicities. Adding those 183 individuals to the AJ group raised the percentage of AJs in the overall population from 1.9% to 2.9%. Figure2 presents the ethnic distribution of our study group.


A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility.

Perreault-Micale C, Davie J, Breton B, Hallam S, Greger V - Mol Genet Genomic Med (2015)

Ethnicity of the study population that included 22,864 individuals from fertility clinics within the United States.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4521971&req=5

fig02: Ethnicity of the study population that included 22,864 individuals from fertility clinics within the United States.
Mentions: 66% of patients reported ethnicity, country of origin, or a combination of both. We used the following ethnic categories: Asian, African-American, AJ, Caucasian (including French Canadian), Hispanic, other (all that did not fall into one of the above categories), and more than one ethnicity. 439 individuals reported AJ as their only ancestry. Since Bloom syndrome is considered to be an AJ disorder, 183 additional participants that reported AJ plus one or more other ethnicity were reassigned to the AJ group. The majority of them (147 individuals) identified themselves as AJ plus Caucasian or specified a country of origin indicative of Caucasian ancestry, such as Germany or Russia. The other 36 reported one or more other additional ethnicities. Adding those 183 individuals to the AJ group raised the percentage of AJs in the overall population from 1.9% to 2.9%. Figure2 presents the ethnic distribution of our study group.

Bottom Line: Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity.The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay.All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria.

View Article: PubMed Central - PubMed

Affiliation: Good Start Genetics, Inc. 237 Putnam Avenue, Cambridge, Massachusetts, 02139.

ABSTRACT
Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic-specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next-generation DNA sequencing (NGS), then affords the capability for an ethnically diverse, comprehensive, highly specific carrier-screening assay. The clinical utility of our approach was demonstrated by screening a pan-ethnic population of 22,864 individuals for Bloom syndrome carrier status using a BLM variant panel comprised of 50 pathogenic variants. In addition to carriers of the common AJ founder variant, we identified 57 carriers of other pathogenic BLM variants. All variants reported had previously been curated and their clinical validity documented, or were of a type that met our stringent, preassigned validity criteria. Thus, it was possible to confidently report an increased number of Bloom's syndrome carriers compared to traditional, ethnicity-based screening, while not reducing the specificity of the screening due to reporting variants of unknown clinical significance.

No MeSH data available.


Related in: MedlinePlus