Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

Beyond the Brochure: Innovations in Clinical Counseling Practices for Prenatal Genetic Testing Options.

Remarkable advancements related to preconception and prenatal genetic screening have emerged in recent years. While technology and testing options are more numerous and complex; fundamental genetic counseling issues remain the same. It is essential that with any prenatal genetic testing, women have an opportunity to make informed and autonomous decisions that are consistent with their personal needs and values. Opportunities to discuss testing options, including potential benefits and limitations, are often limited in obstetric visits due to time constraints or lack of sufficient provider education. As genetic testing is not considered a routine component of antepartum care, review of information regarding testing options is imperative so women can decide which, if any, testing to pursue. Developing new strategies to address the growing complexity of prenatal testing while ensuring provider education is accurate is crucial in imparting evidence-based care. This article will arm providers with the knowledge needed to educate women about currently available prenatal genetic screening and diagnostic tests along with guidance on the essential elements and importance of genetic counseling.

MKS1 regulates ciliary INPP5E levels in Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. METHODS: We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations. RESULTS: We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥ 1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. CONCLUSIONS: MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.

Chorionic Villus Sampling, Early Amniocentesis, and Termination of Pregnancy Without Diagnostic Testing: Comparison of Fetal Risk Following Positive Non-invasive Prenatal Testing.

BACKGROUND: With the increased accuracy of non-invasive prenatal testing (NIPT) based on cell-free DNA (cfDNA) techniques, the likelihood of false-positive screening results has been reduced for high-risk populations. Following a positive screening test, a diagnostic procedure to confirm the result is strongly recommended, although some patients have terminated pregnancies because of a positive NIPT alone. Chorionic villus sampling (CVS), the diagnostic procedure of choice in the first trimester, is not available in all locations. Amniocentesis before 15 weeks, referred to as early amniocentesis (EA), is associated with a 1% rate of talipes and an increased rate of early pregnancy loss compared with CVS. Our objective was to compare the level of risk for euploid pregnancies following a positive NIPT based on the invasive procedure chosen. METHOD: Using data from a 2003 meta-analysis, we estimated the rates of adverse pregnancy outcome in euploid pregnancies based on the positive predictive value (PPV) of NIPT and the invasive procedure used-that is, CVS, EA, or termination of pregnancy (TOP). RESULTS: Following NIPT, we found that the rate of adverse fetal outcomes in euploid pregnancies was lower for CVS than for EA at all PPV levels. As the PPV of NIPT increased, the difference in risk between EA and CVS decreased. The risk to euploid pregnancies of TOP was excessive at all PPVs. CONCLUSION: CVS is the recommended diagnostic test in the first trimester because it is safer than EA for the fetus. However, EA is better than no testing when early TOP is planned. Patients should be strongly counselled against TOP without confirmatory testing.

Noninvasive prenatal testing: limitations and unanswered questions.

The clinical use of noninvasive prenatal testing to screen high-risk patients for fetal aneuploidy is becoming increasingly common. Initial studies have demonstrated high sensitivity and specificity, and there is hope that these tests will result in a reduction of invasive diagnostic procedures as well as their associated risks. Guidelines on the use of this testing in clinical practice have been published; however, data on actual test performance in a clinical setting are lacking, and there are no guidelines on quality control and assurance. The different noninvasive prenatal tests employ complex methodologies, which may be challenging for health-care providers to understand and utilize in counseling patients, particularly as the field continues to evolve. How these new tests should be integrated into current screening programs and their effect on health-care costs remain uncertain.

Maintaining access to maternal fetal medicine care by telemedicine during a global pandemic.

OBJECTIVE: This study aims to compare a conventional medical treatment model with a telehealth platform for Maternal Fetal Medicine (MFM) outpatient care during the global novel coronavirus pandemic. METHODS: In this study, we described the process of converting our MFM clinic from a conventional medical treatment model to a telemedicine platform. We compared clinical productivity between the two models. Outcomes were analysed using standard statistical tests. RESULTS: We suffered three symptomatic COVID-19 infections among our clinical providers and staff prior to the conversion, compared with none after the conversion. We had a significant decrease in patient visits following the conversion (53.35 visits per day versus 40.3 visits per day, p < 0.0001). However, our average daily patient visits per full-time equivalent (FTE) were only marginally reduced (11.1 visit per FTE versus 7.6 visits per FTE, p < 0.0001), resulting in a relative decrease in adjusted work relative value units (6987 versus 5440). There was an increase in more basic follow-up ultrasound procedures, complexity (current procedural technology [CPT] code 76816 (10.7% versus 19.5%, relative risk [RR] 1.81, 95% CI 1.60-2.05, p < 0.0001)) over comprehensive follow-up ultrasound procedures, CPT code 76805 (17.2% versus 7.8%, RR 0.46, 95% CI 0.39-0.53, p < 0.0001) after conversion. Despite similar proportions of new consults, there was an increase in the proportion of follow-up visits and medical decision-making complexity evaluation and management CPT codes (e.g. 99214/99215) after the conversion (17.2% versus 24.6%, RR 1.43, 95% CI 1.26-163, p < 0.0001). There were no differences between amniocentesis procedures performed between the two time periods (0.3% versus 0.2%, p = 0.5805). CONCLUSION: The rapid conversion of an MFM platform from convention medical treatment to telemedicine platform in response to the novel coronavirus pandemic resulted in protection of healthcare personnel and MFM patients, with only a modest decrease in clinical productivity during the initial roll-out. Due to the ongoing threat from the novel coronavirus-19, an MFM telemedicine platform is a practicable and innovative solution and merits the continued support of CMS and health care administrators.

Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.

CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.

Questioning the costs and benefits of non-invasive prenatal testing.

Prenatal testing for Down syndrome through the use of non-invasive prenatal testing (NIPT) has been increasingly implemented in clinical practice and a recent cost analysis suggests that NIPT is cost effective when compared to other screening modalities in high risk populations. However, this anaylsis makes many assumptions regarding uptake of testing and pregnancy termination, which cannot be applied to all populations in the United States. Additionally, this cost analysis, which hinges on fewer Down syndrome births, does not align with the goals of prenatal testing to support autonomous and value consistent decisions. NIPT is an expensive new technology and more careful analysis is needed to determine the impact of NIPT on outcomes and overall healthcare costs.

Improving knowledge about prenatal screening options: can group education make a difference?

OBJECTIVE: To determine if the addition of group education regarding maternal serum screening and diagnostic testing for aneuploidy and neural tube defects improves patient knowledge and affects the uptake of testing compared to individual education alone. METHOD: We conducted a prospective study of 443 obstetric patients to assess knowledge of prenatal testing options based on individual provider counseling (n = 331) or provider counseling with supplemental group education (n = 112). We used a chi-square test to compare the number of correct survey answers between the two groups. RESULTS: There was no difference in baseline knowledge. Patients receiving group education showed a statistically significant improvement in knowledge. After initiation of group education, the uptake of maternal serum screening declined while the uptake of amniocentesis remained unchanged. CONCLUSION: Group education in addition to individual counseling to discuss prenatal testing options appears to be effective in improving knowledge compared to individual provider counseling alone. Improved knowledge may affect uptake of prenatal screening tests due to more informed decision making.