Mobile element insertion detection in 89,874 clinical exomes.

PURPOSE: Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods. METHODS: We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases. RESULTS: Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02-0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08-0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene. CONCLUSION: MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.

An assessment of women's knowledge of and views on the reporting of ultrasound soft markers during the routine anatomy ultrasound examination.

OBJECTIVE: To assess women's knowledge of and views on the evaluation and reporting of ultrasound soft markers. METHODS: A prospective survey of 263 women undergoing 18 to 20 week anatomy ultrasound examination at Mount Sinai Hospital, a level 3 perinatal referral centre for a multi-ethnic population of approximately 2.5 million. RESULTS: Prior to reading an information pamphlet provided in the context of this survey, 30% of women (79/263) reported having heard of the term soft marker and 59% of these women (47/79) had discussed soft markers with their caregiver. When asked their preferences about the reporting of ultrasound soft markers, 53% of women said that soft markers should be reported routinely, 20% said they should be reported when the caregiver thinks it necessary, and 23% preferred they be reported only when they have been discussed prior to the ultrasound examination. A minority of respondents (8%) had not participated in prenatal screening for aneuploidy. All of these women preferred that soft markers be reported only after pre-screening discussion. CONCLUSION: The study demonstrates that most women have little prior knowledge about routine examination for soft markers during the anatomy ultrasound examination and emphasizes the importance of expanding counselling and informed consent to include this aspect of prenatal screening.

Second-trimester prediction of severe placental complications in women with combined elevations in alpha-fetoprotein and human chorionic gonadotrophin.

OBJECTIVE: The purpose of this study was to determine the ability of uterine artery Doppler and placental ultrasound to identify adverse clinical outcomes attributable to severe placental dysfunction in women with second-trimester unexplained elevated maternal serum screening of alpha-fetoprotein and human chorionic gonadotropin. STUDY DESIGN: Fifty singleton pregnancies with elevated alpha-fetoprotein (3.5 multiples of median [range 2.1 to 10.5]) and human chorionic gonadotropin (5.3 multiples of median [range 2.5 to 21.7]) and a normal fetal anatomical ultrasound were prospectively evaluated with placental ultrasound and uterine artery Doppler at referral between 19 and 23 weeks' gestation. RESULTS: Abnormalities in both placental ultrasound and uterine artery Doppler (n = 24) predicted preterm delivery less than 32 weeks from any cause (n = 24) (75% sensitivity, 75% positive predictive value; likelihood ratio positive 3.3 [1.6 to 6.8]), intrauterine fetal death (n = 12) (100% sensitivity, 50% positive predictive value; likelihood ratio positive 3.1 [2.0 to 5.0]), and intrauterine growth restriction with absent/reversed end-diastolic flow (n = 17) (sensitivity 94%, positive predictive value 67%, likelihood ratio positive 3.9 [2.0 to 6.2]) . Ischemic-thrombotic pathology was present in 88% of placentas examined (n = 32). CONCLUSION: Uterine artery Doppler and placental morphology identified most pregnancies with combined abnormal maternal serum screening destined to result in extremely premature delivery and/or perinatal death. Abnormal maternal serum screening reports could include a recommendation for placental ultrasound testing when no fetal explanation has been identified.

Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus.

Myotonic dystrophy, caused by DM1 CTG/CAG repeat expansions, shows varying instability levels between tissues and across ages within patients. We determined DNA replication profiles at the DM1 locus in patient fibroblasts and tissues from DM1 transgenic mice of various ages showing different instability. In patient cells, the repeat is flanked by two replication origins demarcated by CTCF sites, with replication diminished at the expansion. In mice, the expansion replicated from only the downstream origin (CAG as lagging template). In testes from mice of three different ages, replication toward the repeat paused at the earliest age and was relieved at later ages-coinciding with increased instability. Brain, pancreas and thymus replication varied with CpG methylation at DM1 CTCF sites. CTCF sites between progressing forks and repeats reduced replication depending on chromatin. Thus, varying replication progression may affect tissue- and age-specific repeat instability.

The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal recessive inheritance.

The combination of pulmonary agenesis/dysgenesis/hypoplasia, microphthalmia/anophthalmia, and a diaphragmatic defect (agenesis or eventration) is a rare syndrome presumed to have an autosomal recessive mode of inheritance based on a report of affected siblings born to unaffected parents [Seller et al., 1996]. The condition is known as Spear syndrome and Matthew-Wood syndrome, although genetic heterogeneity cannot be ruled out. We report on eight patients with this condition including a living child, three sibs and three isolated cases. Most presented with fetal ultrasound findings of microphthalmia/anophthalmia, and diaphragmatic eventration/hernia and in five, cardiac abnormalities were also found. The earliest detection was at 20 weeks gestation. This is the second report of sibs affected with this condition, which supports an autosomal recessive mode of inheritance. We present the first and only reported living patient with this condition and expand the intrafamilial, interfamilial, and ethnic variability of this condition. We suggest changing the condition's name to PDAC to reflect the most important components of this condition.