{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T17:03:30Z","timestamp":1771002210545,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T00:00:00Z","timestamp":1562716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003189","name":"National Tay-Sachs and Allied Diseases Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pathogenic variants in <jats:italic>HEXA<\/jats:italic> that impair \u03b2\u2010hexosaminidase A (Hex A) enzyme activity cause Tay\u2010Sachs Disease (TSD), a severe autosomal\u2010recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near\u2010zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of <jats:italic>HEXA<\/jats:italic> results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan\u2010ethnic population. The ability to detect <jats:italic>HEXA<\/jats:italic> variants via DNA analysis has evolved from limited targeting of a few ethnicity\u2010specific variants to next\u2010generation sequencing (NGS) of the entire coding region coupled with interpretation of any discovered novel variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We combined results of enzyme testing, retrospective computational analysis, and variant reclassification to estimate the respective clinical performance of TSD screening via enzyme analysis and NGS. We maximized NGS accuracy by reclassifying variants of uncertain significance and compared to the maximum performance of enzyme analysis estimated by calculating ethnicity\u2010specific frequencies of variants known to yield false\u2010positive or false\u2010negative enzyme results (e.g., pseudodeficiency and B1 alleles).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In both AJ and non\u2010AJ populations, the estimated clinical sensitivity, specificity, and positive predictive value were higher by NGS than by enzyme testing. The differences were significant for all comparisons except for AJ clinical sensitivity, where NGS exceeded enzyme testing, but not significantly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results suggest that performance of an NGS\u2010based TSD carrier screen that interrogates the entire coding region and employs novel variant interpretation exceeds that of Hex A enzyme testing, warranting a reconsideration of existing guidelines.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.836","type":"journal-article","created":{"date-parts":[[2019,7,11]],"date-time":"2019-07-11T05:20:03Z","timestamp":1562822403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Screening for Tay\u2010Sachs disease carriers by full\u2010exon sequencing with novel variant interpretation outperforms enzyme testing in a pan\u2010ethnic cohort"],"prefix":"10.1002","volume":"7","author":[{"given":"Alana C.","family":"Cecchi","sequence":"first","affiliation":[{"name":"Myriad Women\u2019s Health South San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth S.","family":"Vengoechea","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristjan E.","family":"Kaseniit","sequence":"additional","affiliation":[{"name":"Myriad Women\u2019s Health South San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3126-5979","authenticated-orcid":false,"given":"Melanie W.","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura 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Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8822-2035","authenticated-orcid":false,"given":"Dale","family":"Muzzey","sequence":"additional","affiliation":[{"name":"Myriad Women\u2019s Health South San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2158-8846","authenticated-orcid":false,"given":"Karen A.","family":"Grinzaid","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,7,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20010215)99:1<70:AID-AJMG1120>3.0.CO;2-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.69"},{"issue":"4","key":"e_1_2_8_4_1","first-page":"733","article-title":"Diagnosis and 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