The evaluation of circulating cell-free DNA by massively parallel shotgun or targeted sequencing to determine the risk of fetal aneuploidy has been rapid and extensive. Recent published studies have demonstrated the incremental value of the use of cell-free DNA for noninvasive prenatal testing (NIPT). 1 Various methods and technologies have been used for NIPT, with impressive results. In one study, NIPT demonstrated 100% sensitivity for both trisomy 21 and trisomy 18, with a specificity of ≥99.7% for both. 1 Data recently presented by two independent groups in 2013 2 and 2014 3 prompted us to review the concordance of results among cases with positive or negative NIPT results referred to Quest Diagnostics for confirmation with cytogenetic studies. MATERIALS AND METHODSWe evaluated the results from 109 consecutive specimens prenatally and/or postnatally studied by standard karyotyping, fluorescence in situ hybridization analysis (AneuVysion; Abbott Molecular/Vysis, Abbott Park, IL), and/or oligo-single-nucleotide polymorphism microarrays (CytoScanHD; Affymetrix, Santa Clara, CA) after NIPT. The NIPT providers were listed in 42 cases and included Panorama (Natera, San Carlos, CA; 20 cases), Harmony (Ariosa Diagnostics, San Jose, CA; 13 cases), MaterniT21 (Sequenom, San Diego, CA; 8 cases), and Verifi (Illumina, Redwood City, CA; 1 case). The most common initial NIPT-positive result was trisomy 21 (41 cases), followed by trisomy 18 (25 cases), trisomy 13 (16 cases), sex chromosome aneuploidy (16 cases), trisomy 16 (3 cases), monosomy 21 (2 cases), and 1 case each of triploidy and microdeletion of 22q11.2. Four samples negative for NIPT but positive for ultrasound findings were included. RESULTSCytogenetic results were positive for trisomy 21 in 38 of the 41 NIPT-positive cases (true-positive rate: 93%) and for trisomy 18 in 16 of the 25 NIPT-positive cases (true-positive rate: 64%) ( Table 1). The true-positive rate was only 44% (7/16 cases) for trisomy 13 and 38% (6/16 cases) for sex chromosome aneuploidy. A total of six cases with positive NIPT results for either monosomy 21, trisomy 16, triploidy, or 22q11.2 microdeletion had normal cytogenetic findings. Only one case had very-lowlevel mosaicism (~5-10%) for trisomy 16. Confined placental mosaicism was confirmed in two cases (2/105, 2%): one with 3% mosaic for trisomy 18 and another with a mosaic segmental uniparental disomy for 11p15.5-p11.2. A false-negative result for NIPT was identified in nonmosaic trisomies 9 and 21, a marker chromosome, and a mosaic sex chromosome aneuploidy.The findings from our laboratory and those presented by the above-mentioned two groups (n = 80 and n = 46) show that Purpose: Recent published studies have demonstrated the incremental value of the use of cell-free DNA for noninvasive prenatal testing with 100% sensitivity for trisomies 21 and 18 and a specificity of ≥99.7% for both. Data presented by two independent groups suggesting positive results by noninvasive prenatal testing were not confirmed by cytogenetic studies. Methods:C...

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p<0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

Intracranial and extracranial anomalies were good predictors of neurodevelopmental outcome in this study. The prognosis was poor for individuals with an abnormal brainstem, whereas those with isolated MCM had normal neurodevelopmental outcome.

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In an effort to increase the diversity of the membership of the National Society of Genetic Counselors (NSGC), the Membership Committee provided two $500 scholarships to genetic counseling students planning to attend the NSGC AEC meeting in Dallas, Texas in October 2010. Requirements for applicants of both scholarships included enrollment in the fall of 2010, good standing at an accredited genetic counseling training program, and NSGC membership or plans to join in 2011. Students who are from communities underrepresented in the NSGC, including, but not limited to, those of minority cultural/ethnic backgrounds and those with disabilities were eligible to apply for the "Diversity" scholarship. Students from all backgrounds who have an interest in diversity issues were eligible to apply for the "General" scholarship. Applicants wrote essays 1000 words or less answering the following questions: How has your identity as a member of a group underrepresented in the genetic counseling profession affected your pursuit of this career? What do you feel is lacking in genetic counseling to address the issues of underrepresented groups? What strategies do you recommend for addressing these issues and/or increasing diversity? Why do you think diversity is an important issue for the field of genetic counseling? What strategies do you recommend to attract and retain students, especially those from underrepresented populations, into the field of genetic counseling? How do you envision contributing to these strategies? The essays by the award recipients elucidated interesting perspectives and ideas for increasing diversity in the genetic counseling profession.