Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

The uptake of pan-ethnic expanded carrier screening is higher when offered during preconception or early prenatal genetic counseling.

OBJECTIVE: To examine factors that influence uptake of expanded carrier screening (ECS) among women undergoing preconception and prenatal genetic counseling. METHODS: We retrospectively reviewed 500 medical records from women with prenatal or preconception genetic counseling at a prenatal genetic counseling service. We tabulated acceptance of ECS by indication for genetic counseling along with demographic and pregnancy-related factors. RESULTS: ECS was offered to 483 of 500 women, and 192 (39.8%) accepted. Of the 67 women counseled preconceptionally, 46 (68.7%) accepted ECS. This was significantly more than for 416 women counseled during pregnancy, of whom 146 (35.1%) accepted (P ≤ 0.001). For pregnant patients, the mean gestational age of those accepting ECS (12 weeks 3 days; n = 146) was significantly lower than those declining (13 weeks 4 days; n = 270; P ≤ 0.001). The acceptance rates were 7 of 12 (58.3%, P = 0.195) for Ashkenazi Jewish women, 12 of 41 (29.3%; P = 0.186) for Asian women, and 7 of 25 (28.0%; P = 0.241) for women of mixed ethnicity. CONCLUSIONS: These results suggest that receiving genetic counseling prior to or earlier in the first trimester is associated with acceptance of ECS and support the importance of early genetic counseling about carrier screening options.

Missed opportunities: unidentified genetic risk factors in prenatal care.

OBJECTIVE: Prenatal and preconception care guidelines recommend obtaining family history to screen for reproductive genetic risk. The effectiveness of this screening and subsequent referral for genetic counseling is not well established. This study describes how often pregnant women with reproductive genetic risks were not referred for prenatal genetic counseling and the indications frequently missed. METHOD: We retrospectively reviewed genetic consultation medical records for first-trimester screen pretest counseling. These women had no documented indications for genetic counseling. We used the American College of Medical Genetics and Genomics referral guidelines for genetic counseling to identify missed indications within the parents' personal and family histories. Patients with advanced maternal age were excluded. RESULTS: We reviewed 416 consultation notes. The counselor elicited a genetic risk for which a referral had not been made in 27% of the pregnant women. Of these, 70% were genetic risks in the family history, 23% in the couple's history, and 7% in the prenatal history. The most common missed indications were personal or family history of birth defects (38%), intellectual disability or autism (19%), and a prior positive genetic carrier screening test (14%). CONCLUSION: Genetic risk factors are not consistently identified as a referral indication for reproductive genetic counseling. © 2017 John Wiley & Sons, Ltd.

Copy-number changes in prenatal diagnosis.

Until recently, the prenatal detection of genetic disease was available to only a subset of the pregnant population deemed to be at an increased risk for chromosomal abnormalities or, more rarely, other genetic disorders, based on family history, multiple-marker screening or ultrasound findings. Guided by recent data that indicate that screening for Down syndrome has improved and that risks of invasive procedures are smaller than previously ascertained, the American College of Obstetricians and Gynecologists has recommended that all women have access to invasive prenatal diagnosis. The parallel development of newer genetic diagnostic technologies, such as chromosomal microarray analysis, has made it feasible to simultaneously test for more conditions than was possible with standard karyotype analysis complemented by targeted fluorescence in situ hybridization or mutation detection for specific conditions. In the pediatric and adult population, chromosomal microarray analysis has already been thoroughly evaluated and is now recommended as a first-line diagnostic test for clinically suspected genetic disorders. In this article, we review the current status of array-based comparative genomic hybridization use for prenatal diagnosis and predict that, in the future, it will replace karyotyping as a first-line test for detecting chromosomal abnormalities in the prenatal setting.

Dichorionic twins discordant for thanatophoric dysplasia managed with selective reduction at 20 weeks' gestation: a case report.

BACKGROUND: Thanatophoric dysplasia (TD) is a rare and lethal form of skeletal disorder. A MEDLINE search for 1965-2003 yielded only 3 reports of multiple pregnancies discordant for TD. This is the first case report of selective twin reduction for this diagnosis. CASE: A young woman was seen in consultation at 20 weeks' gestation. Ultrasound examination revealed a twin pregnancy, with ultrasound markers consistent with thanatophoric dysplasia, type II, in twin A. A thick dividing membrane and separated placentas were noted. After counseling, the patient opted for selective termination of twin A. Termination was performed by intracardiac injection of potassium chloride. The pregnancy continued uneventfully until 33 weeks, when spontaneous labor resulted in vaginal delivery of a vigorous female infant, and a mummified, macerated fetus. CONCLUSION: Selective termination for discordant lethal anomalies can be safely performed when the presence of the anomalous twin increases the risk of a poor perinatal outcome for the apparently normal cotwin.

Pittsburgh Registry of Infant Multiplets (PRIM).

This paper describes the Pittsburgh Registry of Infant Multiplets (PRIM; Pittsburgh, Pennsylvania), the results of pilot research conducted in this registry, and the plans for future studies. The main focus of the registry is on psychological development and the risk for behavioral disorders. Particularly, characteristics associated with antisociality and the risk for substance use disorders (e.g., aggressivity, hyperactivity/impulsivity), as well as language development and other traits (e.g., dental health) are among the research targets.