Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Depression and socioeconomic stressors in expectant parents with fetal congenital anomalies.

OBJECTIVE: Congenital anomalies are increasingly diagnosed before birth, which may lead to psychological distress in expectant parents. While the presence of significant symptoms of depression and stress in these parents is established, understanding their context within parents' other life stressors has not been fully investigated. We sought to characterize the socioeconomic profile and depression symptoms of expectant parents in a quaternary care academic hospital's fetal care clinic. METHODS: This prospective observational study enrolled pregnant persons and their partners in our fetal care clinic. The Edinburgh Postpartum Depression Scale (EPDS), Tool Assessing Patient Stress (TAPS), and a sociodemographic survey were utilized to assess parent psychological distress and socioeconomic stressors. Results were analyzed by the severity of the fetal anomaly. EPDS was repeated at two weeks postpartum. RESULTS: 21.7% of pregnant subjects and 25.0% of co-parents had a positive screen on the EPDS at enrollment during their pregnancy. Mothers' EPDS scores correlated with the severity of the fetal anomaly. Many parents reported socioeconomic stressors including: living remotely from the medical center, low household income, food insecurity, unemployment, or other employment concerns, and difficulty affording living expenses. Most also reported factors that can mitigate psychological distress including social support and participation in a religion or faith. CONCLUSIONS: Expectant parents with fetal anomalies should be screened for depression as well as social and economic risk factors that place them and their infants at higher risk for poor health outcomes. Further work is needed to determine the optimum interventions for addressing their depression symptoms and reducing socioeconomic stressors.

Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors.

Down syndrome is one of the most common conditions encountered in the genetics clinic. Due to improvements in healthcare, educational opportunities, and community inclusion over the past 30 years, the life expectancy and quality of life for individuals with Down syndrome have significantly improved. As prenatal screening and diagnostic techniques have become more enhanced and widely available, genetic counselors can expect to frequently provide information and support following a new diagnosis of Down syndrome. This guideline was written for genetic counselors and other healthcare providers regarding the communication of a diagnosis of Down syndrome to ensure that families are consistently given up-to-date and balanced information about the condition, delivered in a supportive and respectful manner.

A Deep Intronic Variant Activates a Pseudoexon in the MTM1 Gene in a Family with X-Linked Myotubular Myopathy.

We report a novel intronic variant in the MTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5' donor splice site resulting in the inclusion of a 48-bp pseudoexon into the mature MTM1 mRNA. The variant is present in all affected males, absent in unaffected males, and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon, and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediated decay. We conclude that affected males produce no, or low, levels of MTM1 mRNA likely leading to a significant reduction of myotubularin-1 protein resulting in the severe neonatal myopathy present in this family. The study highlights the need to consider noncoding variants in genomic screening in families with X-linked myotubular myopathy.

STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells.

Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca2+ influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca2+ channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca2+ influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non-pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell-mediated inflammatory diseases.

Monozygotic dichorionic diamniotic twins with large interstitial deletion of chromosome 1p.

We describe twins with an interstitial deletion of chromosome 1 with a severe phenotype compared to previously described cases. As genetic testing is more frequently performed, it is important for clinicians to understand the spectrum of clinical findings that can occur with this particular deletion.

Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia.

This study aimed to identify the genetic basis of a severe skeletal lethal dysplasia. The main clinical features of two affected fetuses included short limbs with flared metaphyses, bowed radii, femora and tibiae, irregular ossification of hands and feet, and marked platyspondyly. Affected and nonaffected family members were subjected to whole-exome sequencing, followed by immunoblot analysis on amniocytes isolated from one of the affected individuals. Unique compound heterozygous variants in the inositol polyphosphate phosphatase-like 1 (INPPL1) gene encoding the SHIP2 protein were identified in both affected individuals. One variant was inherited from each unaffected parent. Both allelic variants, c.(2327-1G>C);(1150_1151delGA), are predicted to result in premature stop codons leading to nonsense-mediated mRNA decay of the mutant alleles and no production of SHIP2. The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes. This skeletal disorder is caused by the complete absence of the SHIP2 protein. INPPL1 mutations have been reported in opsismodysplasia, an autosomal recessive skeletal dysplasias with significant delayed bone formation. Our finding highlights the critical role that INPPL1/SHIP2 plays in skeletal development.

Jacobsen syndrome detected by noninvasive prenatal testing.

BACKGROUND: Noninvasive prenatal testing has a high detection rate of common fetal chromosomal aneuploidies. However, detection of additional chromosome abnormalities has not been well described or validated. CASE: We report a case of Jacobsen syndrome, a congenital disorder involving deletion of chromosome 11q, detected by noninvasive prenatal testing at 14 weeks of gestation and confirmed on neonatal testing with array chromosomal genomic hybridization. CONCLUSION: Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing.

Chromosomal microarray analysis and prenatal diagnosis.

Chromosomal microarray analysis (CMA) assesses chromosomal copy number alterations and affords higher resolution when compared with standard karyotype. This review provides the obstetric provider with an update on the technology, use, and controversies concerning CMA utilization in prenatal diagnosis. Chromosomal microarray analysis offers increased resolution for copy number abnormalities compared with traditional karyotype. There is high-quality evidence for the added detection of clinically significant copy number alterations with CMA in prenatal diagnosis when the traditional karyotype is normal. Other potential advantages of CMA include a quicker turnaround time and utilization in clinical situations with a high probability of nondividing cells (ie, intrauterine fetal demise, spontaneous miscarriage, and third-trimester amniocentesis). Chromosomal microarray analysis may be beneficial when prenatally detected structural anomalies are associated with specific microdeletions and microduplications or to assess for copy number variants when a de novo balanced rearrangement or marker chromosome is diagnosed. Use of CMA includes the detection of copy number variants of uncertain significance. In light of these issues, large prospective cohort studies are needed to illustrate the diagnostic utility of CMA for detection of prenatal chromosomal abnormalities in low-risk populations before routine clinical use of CMA is recommended in all circumstances of prenatal diagnosis.

Chorionic villus sampling for abnormal screening compared to historical indications: prevalence of abnormal karyotypes.

OBJECTIVE: To determine the prevalence of abnormal karyotype results in women undergoing chorionic villus sampling (CVS) for abnormal first trimester screening compared to CVS for historical indications (advanced maternal age (AMA) or prior aneuploidy). METHODS: Retrospective cohort of all patients undergoing CVS at Oregon Health & Science University from January 2006 to June 2010. Patients were separated based on CVS indication: (1) positive ultrasound (U/S) or serum screening; or (2) AMA or prior aneuploidy with normal or no screening. Prevalence of abnormal karyotype results were compared between groups. RESULTS: Fetal karyotyping was successful in 500 of 506 CVS procedures performed. 203 CVS were performed for positive screening with 69 abnormal karyotypes (34.0%). 264 CVS were performed for historical indications with 11 abnormal karyotypes (4.2%). This difference was statistically significant (χ(2) 71.9, p < 0.001; OR 11.8 [95% CI 5.8, 24.6]). There were two age-related aneuplodies in AMA women without positive screening. 42 out of 44 AMA women diagnosed with aneuploidy (95.5%) had abnormal U/S and/or serum screening (35 U/S, 4 serum, 3 U/S and serum). CONCLUSIONS: Combined ultrasound and serum screening should be recommended to all women, including AMA women, prior to undergoing invasive testing to improve risk-based counseling and minimize morbidity.