What are the novel findings of this work? This study is the first to directly explore pregnancy outcomes following noninvasive prenatal screening (NIPS) on samples with low fetal fraction (FF). On most NIPS offerings, low-FF samples are failed, yet we find that a customized NIPS that does not fail samples based on FF has comparable sensitivity and specificity for high-and low-FF samples. What are the clinical implications of this work? Test failures due to low fetal fraction (FF) during noninvasive prenatal screening (NIPS) increase patient anxiety, lengthen the prenatal screening process, and complicate provider workflow. Our study shows that a customized NIPS based upon whole-genome sequencing performs comparably at high and low FF, rendering low-FF test failures unnecessary.
Objective Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.Methods Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. ResultsThe SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. ConclusionThe WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures.
CONFLICT OF INTERESTS:All authors other than YY are employees of Counsyl Inc., a company that performs noninvasive prenatal screening. YY is a clinical expert panel member for Illumina Inc., a company that performs noninvasive prenatal screening, and a consultant for Teva Pharmaceuticals, a local distributor of noninvasive prenatal 30 screening. Abstract 60Objective Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) 65 method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.Methods Computational models were parameterized with up-to-date published data 70 and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. 75Results The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. 80 ConclusionThe WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. 85
Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene. Mutations have been demonstrated in more than 80% of females with typical features of Rett syndrome. We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum. Bidirectional sequencing of the entire MECP2 coding region was performed. We diagnosed 65 patients with MECP2 mutations. Of these, 15 mutations had been reported previously and 13 are novel. Two patients have multiple deletions within the MECP2 gene. Eight common mutations were found in 43 of 65 patients (66.15%). The majority of patients with identified mutations have the classic Rett phenotype, and several had atypical phenotypes. MECP2 analysis identified mutations in almost all cases of typical Rett syndrome, as well as in some with atypical phenotypes. Eleven (20.4%) of the 54 patients with defined mutations and in whom phenotypic data were obtained did not develop acquired microcephaly. Hence, microcephaly at birth or absence of acquired microcephaly does not obviate the need for MECP2 analysis. We have initiated cascade testing starting with PCR analysis for common mutations followed by sequencing, when necessary. Analysis of common mutations before sequencing the entire gene is anticipated to be the most efficacious strategy to identify Rett syndrome gene mutations.
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