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703: Non-invasive prenatal diagnosis of trisomy 21: replacing invasive testing or replacing screening?
www.AJOG.org
Academic Issues, Antepartum Fetal Assessment, Genetics, Hypertension, Medical-Surgical-Disease
Poster Session V
ing, including potential differences in testing recommendations by obstetrical care providers.
704 Prenatal testing for Noonan spectrum disorders using a multi-gene sequencing panel in fetuses with abnormal ultrasound findings Elizabeth Kramer1, Bradley Williams1, Swaroop Aradhya1, Isabelle Olivos-Glander1, Gabriele Richard1, Eden Haverfield1, Jeanne Meck1 1
GeneDx, Prenatal Diagnostic Services, Gaithersburg, MD
OBJECTIVE: To determine the frequency and range of mutations in
703 Non-invasive prenatal diagnosis of trisomy 21: replacing invasive testing or replacing screening? E.J. (Joanne) Verweij1, Marjon de Boer1, Phebe N. Adama van Scheltema1, Jessica M.E. van den Oever2, Elles M.J. Boon2, Dick Oepkes1 1 Leiden University Medical Center, Department of Obstetrics, Leiden, Netherlands, 2Leiden University Medical Center, Center for Human and Clinical Genetics, Leiden, Netherlands
OBJECTIVE: Non-invasive prenatal diagnosis (NIPD) of trisomy 21 (T21) is now a clinical reality. Implementation will result in a drastic reduction of invasive diagnostic tests. Whether NIPD should be used as first line screening, replacing first trimester serum screening and NT measurement (combination test, CT), or only for high risk pregnancies is subject of debate. Aim of our study was to compare the overall impact of NIPD as a substitute for invasive testing versus NIPD replacing CT. STUDY DESIGN: Based on the national population based dataset we constructed two models for the two NIPD implementation options. Sensitivity for CT in our population is 80%, false positive rate 5%, for NIPD these were set at 99% and 0.5% respectively. Natural loss after 12 wks of T21 was set at 30%. Invasive procedures were requested in 90%. Termination of T21 pregnancy was requested in 90%. Additional risk of miscarriage after invasive testing was set at 0.5%. The uptake of the 20 week anomaly scan is almost 100%. Primary outcome was the miscarriage/detection rate for aneuploidies. Secondary outcome was the effect on rate of live born children with chromosomal abnormalities. RESULTS: In table 1 the two models for NIPD and the existing pathway are compared for detection of trisomic chromosomal abnormalities and procedure-related miscarriage in case of an uptake of the test of 30, 50 or 80%. CONCLUSION: Both models result in an impressive decline in procedure-related miscarriages as we predict a major reduction in the number of invasive procedures. The use of NIPD as first line screening results in the lowest miscarriage/detection rate. Non-trisomic chromosomal abnormalities, mostly sex chromosome abberations, found by full karyotyping, not detected by ultrasound will be missed in 6% when NIPD would be implemented. Clinical importance of these unexpected findings is questionable.
Noonan spectrum disorders in fetuses with ultrasound abnormalities. STUDY DESIGN: 212 pregnancies with abnormal fetal sonogram, most with normal chromosome and/or array results, were referred for prenatal diagnostic testing for Noonan syndrome. The average gestational age was 16 wks. Testing was performed on cultured CVS or amniocytes using a 9 gene panel, which interrogates the complete coding regions of PTPN11 and 7 other genes in the RAS/MAPK pathway and 1 common mutation in SHOC2. RESULTS: The most common test indications were increased nuchal translucency (NT) (33%), cystic hygroma (42%), and/or hydrops, pleural effusion, and congenital heart malformations. A known pathogenic mutation was identified in 13/212 fetuses (6%), at least 8 of whom had a de novo mutation. Mutations were detected in genes associated with Noonan (PTPN11: n⫽5, SOS1: n⫽2, RAF1: n⫽1, KRAS: n⫽1), but also in those causing Cardio-Facio-Cutaneous (CFC) (BRAF: n⫽1, MAP2K1: n⫽2) and Costello syndromes (HRAS: n⫽1). Another 8 fetuses (4%) had a variant of uncertain significance, 6 of which were likely benign, based on the nature of the amino acid change and inheritance from an unaffected parent. Of the 13 mutation-positive fetuses, 11 (85%) had cystic hygroma and two (15%) had increased NT (5mm/8mm). The fetuses with a novel, likely disease-causing variant also had cystic hygroma and one of them had a heart defect. CONCLUSION: In 212 fetuses with ultrasound abnormalities, 6% had a known causative mutation associated with a Noonan spectrum disorder. A mutation was identified in 12% and 3% of fetuses with cystic hygroma and increased NT, respectively, confirming that cystic hygroma is the most predictive sonographic sign of these disorders. Mutations in PTPN11 were most prevalent. Nevertheless, the presence of mutations in 6 other genes demonstrates that Noonan, CFC and Costello syndromes can all present with similar prenatal findings and underscores the clinical utility of a comprehensive, multi-gene sequencing approach in the prenatal diagnosis of these disorders.
Supplement to JANUARY 2012 American Journal of Obstetrics & Gynecology
S313
Academic Issues, Antepartum Fetal Assessment, Genetics, Hypertension, Medical-Surgical-Disease
Poster Session V
ing, including potential differences in testing recommendations by obstetrical care providers.
704 Prenatal testing for Noonan spectrum disorders using a multi-gene sequencing panel in fetuses with abnormal ultrasound findings Elizabeth Kramer1, Bradley Williams1, Swaroop Aradhya1, Isabelle Olivos-Glander1, Gabriele Richard1, Eden Haverfield1, Jeanne Meck1 1
GeneDx, Prenatal Diagnostic Services, Gaithersburg, MD
OBJECTIVE: To determine the frequency and range of mutations in
703 Non-invasive prenatal diagnosis of trisomy 21: replacing invasive testing or replacing screening? E.J. (Joanne) Verweij1, Marjon de Boer1, Phebe N. Adama van Scheltema1, Jessica M.E. van den Oever2, Elles M.J. Boon2, Dick Oepkes1 1 Leiden University Medical Center, Department of Obstetrics, Leiden, Netherlands, 2Leiden University Medical Center, Center for Human and Clinical Genetics, Leiden, Netherlands
OBJECTIVE: Non-invasive prenatal diagnosis (NIPD) of trisomy 21 (T21) is now a clinical reality. Implementation will result in a drastic reduction of invasive diagnostic tests. Whether NIPD should be used as first line screening, replacing first trimester serum screening and NT measurement (combination test, CT), or only for high risk pregnancies is subject of debate. Aim of our study was to compare the overall impact of NIPD as a substitute for invasive testing versus NIPD replacing CT. STUDY DESIGN: Based on the national population based dataset we constructed two models for the two NIPD implementation options. Sensitivity for CT in our population is 80%, false positive rate 5%, for NIPD these were set at 99% and 0.5% respectively. Natural loss after 12 wks of T21 was set at 30%. Invasive procedures were requested in 90%. Termination of T21 pregnancy was requested in 90%. Additional risk of miscarriage after invasive testing was set at 0.5%. The uptake of the 20 week anomaly scan is almost 100%. Primary outcome was the miscarriage/detection rate for aneuploidies. Secondary outcome was the effect on rate of live born children with chromosomal abnormalities. RESULTS: In table 1 the two models for NIPD and the existing pathway are compared for detection of trisomic chromosomal abnormalities and procedure-related miscarriage in case of an uptake of the test of 30, 50 or 80%. CONCLUSION: Both models result in an impressive decline in procedure-related miscarriages as we predict a major reduction in the number of invasive procedures. The use of NIPD as first line screening results in the lowest miscarriage/detection rate. Non-trisomic chromosomal abnormalities, mostly sex chromosome abberations, found by full karyotyping, not detected by ultrasound will be missed in 6% when NIPD would be implemented. Clinical importance of these unexpected findings is questionable.
Noonan spectrum disorders in fetuses with ultrasound abnormalities. STUDY DESIGN: 212 pregnancies with abnormal fetal sonogram, most with normal chromosome and/or array results, were referred for prenatal diagnostic testing for Noonan syndrome. The average gestational age was 16 wks. Testing was performed on cultured CVS or amniocytes using a 9 gene panel, which interrogates the complete coding regions of PTPN11 and 7 other genes in the RAS/MAPK pathway and 1 common mutation in SHOC2. RESULTS: The most common test indications were increased nuchal translucency (NT) (33%), cystic hygroma (42%), and/or hydrops, pleural effusion, and congenital heart malformations. A known pathogenic mutation was identified in 13/212 fetuses (6%), at least 8 of whom had a de novo mutation. Mutations were detected in genes associated with Noonan (PTPN11: n⫽5, SOS1: n⫽2, RAF1: n⫽1, KRAS: n⫽1), but also in those causing Cardio-Facio-Cutaneous (CFC) (BRAF: n⫽1, MAP2K1: n⫽2) and Costello syndromes (HRAS: n⫽1). Another 8 fetuses (4%) had a variant of uncertain significance, 6 of which were likely benign, based on the nature of the amino acid change and inheritance from an unaffected parent. Of the 13 mutation-positive fetuses, 11 (85%) had cystic hygroma and two (15%) had increased NT (5mm/8mm). The fetuses with a novel, likely disease-causing variant also had cystic hygroma and one of them had a heart defect. CONCLUSION: In 212 fetuses with ultrasound abnormalities, 6% had a known causative mutation associated with a Noonan spectrum disorder. A mutation was identified in 12% and 3% of fetuses with cystic hygroma and increased NT, respectively, confirming that cystic hygroma is the most predictive sonographic sign of these disorders. Mutations in PTPN11 were most prevalent. Nevertheless, the presence of mutations in 6 other genes demonstrates that Noonan, CFC and Costello syndromes can all present with similar prenatal findings and underscores the clinical utility of a comprehensive, multi-gene sequencing approach in the prenatal diagnosis of these disorders.
Supplement to JANUARY 2012 American Journal of Obstetrics & Gynecology
S313