Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females.

BACKGROUND: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. METHODS AND RESULTS: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama-Klein-Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. CONCLUSIONS: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders.

Selective perfusion of coronary vasculature in preterm sheep: a methodological innovation undermined by unfavourable operation of the foramen ovale.

Antenatal cardiac intervention affords new prospects for hypoplastic left heart syndrome. Its success, however, may come not only from absence of impediments to blood flow but also from a sufficiently developed cardiac wall. Here, we examined the feasibility to perfuse selectively the fetal coronary circulation for treatment with growth promoting agents. Pregnant sheep (94-114 days gestation, term 145 days) were used. An aortic stop-flow procedure was developed for intracoronary access in the nonexposed fetus and human mesenchymal stem cells and their exosomes served as test agents. We found that aortic stop-flow ensures preferential distribution of fluorescent microspheres to the heart. However, intracoronary administration of stem cells or exosomes was detrimental, with fetal demise occurring around surgery or at variable intervals afterwards. Coincidentally, stop-flow caused by itself a marked rise of intraluminal pressure within the occluded aorta along with histological signs of coronary obstruction. We conclude that it is feasible to perfuse selectively the coronary circulation of the preterm fetus, but treatments are not compatible with survival of the animals. The cause for failure is found in the absence of hemodynamic compensation to stop-flow via a left-to-right shunt. This unexpected event is attributed to a largely membranous foramen ovale, characteristic of sheep, that collapses under pressure.

Metatropic dysplasia in third trimester of pregnancy and a novel causative variant in the TRPV4 gene.

Prenatal diagnosis of skeletal dysplasias is particularly difficult for many reasons and differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomonic for a specific disorder. The diagnosis is often made just after birth or exitus. The prenatal diagnosis of osteochondrodysplasias is based predominantly upon fetal ultrasound findings and it focuses substantially on the possible lethality of the disorder, without always being able to find a specific name for the disorder. Metatropic dysplasia is a rare osteochondrodysplasia due to mutations in the TRPV4 gene: TRPV4 is a cation channel, non-selectively permeable to calcium, encoded by a gene on chromosome 12q24.11; it is widely expressed and involved in many different physiological processes through responses to several different stimuli (physical, chemical, and hormonal) in ciliated epithelial cells. The exact incidence of this disorder is not known, however less than a hundred cases have been reported at present, with only two prenatal reports but without any reference to the molecular test. We describe the first report of molecular diagnosis of metatropic dysplasia carried out in prenatal diagnosis: the molecular testing of the TRPV4 (transient receptor potential cation channel, subfamily V, member 4, MIM *605427) gene in our case, in fact, detected a causative variant, confirming the diagnostic suspicion, which was made possible thanks also to the utilization of MRI and CT scan. In our case different imaging methods together with the close cooperation of a multidisciplinary team and test availability, allowed an accurate diagnosis.

Fetal thymus: visualization rate and volume by integrating 2D- and 3D-ultrasound during 2nd trimester echocardiography.

OBJECTIVE: To assess the visualization rate and transverse diameter of fetal thymus by two-dimensional ultrasound (2DUS) as well as the fetal thymus volume by three-dimensional ultrasound (3DUS) during the 2nd trimester echocardiography. METHODS: A prospective cross-sectional study involving 100 normal fetuses between 18w0d and 23w6d was performed. The identification of fetal thymus and peri-thymic vessels was realized at level of three vessels and trachea (3VT). The transverse diameter was obtained placing a line cursor perpendicular to the line connecting the sternum and the spine. The fetal thymus volume was obtained by virtual organ computer-aided analysis (VOCAL) with 30° of rotation. We used the percentage of visualization rate of 2D structures and means and 95% confidence intervals (CI) for fetal thymus transverse diameter and volume. RESULTS: The visualization rate of fetal thymus by 2DUS was of 100% in all gestational ages using the 3VT view. Addition of color Doppler ultrasound facilitates identification of the thy-box and enhanced the calculation of both fetal thymus transverse diameter and volume. The mean fetal thymus transverse diameter by 2DUS ranged from 11 mm at 18 weeks to 19 mm at 23 weeks of gestation. The mean fetal thymus volume by 3DUS ranged from 1.25 cm(3) at 18 weeks to 2.61 cm(3) at 23 weeks of gestation. CONCLUSION: We demonstrated a high visualization rate of fetal thymus and peri-thymic vessels by 2DUS during the 2nd trimester echocardiography. The measurements of transverse diameter by 2DUS and the volume by 3DUS also showed a high success rate.

Prenatal diagnosis of X-linked adrenoleukodystrophy associated with isolated pericardial effusion.

This is the first reported case of fetal pericardial effusion in association with X-linked adrenoleukodystrophy and hypocortisolism from a nonautoimmune cause. Our hypothesis is that in experienced hands and after accurate genetic counseling, isolated pericardial effusion can constitute an indication for a severe metabolic disease.

Prevalence and prenatal ultrasound detection of clubfoot in a non-selected population: an analysis of 549, 931 births in Tuscany.

OBJECTIVE: To evaluate the prevalence and prenatal ultrasound detection of clubfoot in Tuscany during a period of 20 years. METHODS: This is a descriptive analysis on data from the Tuscan register of congenital defects, covering a 20-year period from 1992 to 2011. The Tuscan registry of congenital defects is a population-based register for the epidemiologic surveillance of congenital anomalies. The study included all cases of pre- or postnatally diagnosed clubfoot (isolated clubfoot and cases associated with other congenital defects). Overall prevalence and pre-natal detection rates were calculated. RESULTS: Among the 549,931 deliveries recorded in Tuscany between 1992 and 2011, 858 cases of clubfoot were registered, with a prevalence of 1.56/1000. Seventy-eight percent of cases were isolated. The detection rate was higher when the defect was associated with other anomalies compared to isolated forms. Over the study period, there was a substantial improvement in the prenatal detection of clubfoot (from 11 to 31% overall). For isolated forms, detection rate improved from 4 to 16%, and for cases associated with other congenital defects, it increased from 43 to 73%. CONCLUSION: Prevalence of clubfoot in Tuscany is 1.56 per 1000 births, in agreement with the incidence reported in epidemiological studies in Europe. Prenatal detection of clubfoot improved over time. The detection rate was higher in cases associated with other anomalies.