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PathogenicACTBandACTG1gene variants, encoding the actin isoformsβCYA andγCYA, respectively, are frequently associated with theBaraitser-Winter-CerebroFrontoFacial syndrome (BWCFF-S) that includes malformations of cortical development. Here we explore whether cerebral organoids grown from BWCFF-S patient-derived induced pluripotent stem cells can provide insight into the pathogenesis underlying the cortical malformations of these patients. Cerebral organoids expressing either anACTBor anACTG1gene variant, each with a point mutation resulting in a single amino acid substitution, are reduced in size, showing smaller ventricle-like structures with a thinner ventricular zone (VZ). This decrease in VZ- progenitors is associated with a striking change in the orientation of their cleavage plane from predominantly vertical (control) to predominantly horizontal (BWCFF-S), which is incompatible with increasing VZ-progenitor abundance. The underlying cause appears to be an altered subcellular tubulin localization due to the actin mutations that affects mitotic spindle positioning of VZ-progenitors in BWCFF-S.

The choroid plexus (ChP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the ChP epithelium (ChPe) arises from the Wnt-expressing cortical hem. Embryonic mouse and human ChPe both express nuclear β-CATENIN, a canonical Wnt signaling pathway effector, indicating that this pathway is active during ChPe development. Point mutations in human β-CATENIN result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of ChPe identity and an apparent transformation of the ChPe to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. The ChPe is also disrupted when β-Catenin is conditionally inactivated in the mouse. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal ChPe development in the mammalian brain.

Introduction: The FLNA gene provides instructions for producing protein filamin A. It is found on the X chromosome and has X linked inheritance. The dysfunction of this gene is associated with congenital malformation of the cerebral cortex, cardiac abnormalities, thoracic aneurism and joint hypermobility. Case report: We present a family with heterozygous pathogenic variant of FLNA. Disease was discovered during workup of older daughter’s miscarriages. She had a double miscarriage in the first trimester. She knew for mild mitral and aortic regurgitation from youth. From family history: mother had two miscarriages and two successful deliveries, pulmonary hypertension, coronary artery disease and percutaneous coronary intervention at the age of 56, grandmother from mother side had one successful delivery and three miscarriages, died at the age of 64 from diabetic coma. Sister has moderate aortic regurgitation, dilatation of ascending aorta (42mm), one miscarriage. Father has dilatation of ascending aorta. In 2020. echocardiography revealed dilatation of the ascending aorta (43mm) with mild central aortic regurgitation, and a trace of mitral regurgitation. The cardiologist recommended CT aortography and genetic testing. On CT aortography aorta was measured at a maximum of 46mm. Genetic testing identified one pathogenic variant in FLNA. After this discovery, genetic testing was performed on all family members, and mutation was identified in the mother and sister. During this workup, the younger sister found out that she was pregnant. Soon, the mother suddenly died at the age of 60. Autopsy revealed a dissection of the thoracic aorta. With this finding, the younger sister went from category three to category four in classification of maternal cardiovascular risk score and was advised to abort. At the time of writing this paper she is 10 weeks pregnant and, knowing all the risks, does not want an abortion. Conclusion: In young women with dilatation of ascending aorta, connective tissue disease should be considered. Today we have possibility for family screening, so we can discover pathogenic mutation in families. In FLNA mutation, safe size of ascending aorta dilatation is smaller than in healthy population, which should be considered during pregnancy planning. In case of pregnancy multidisciplinary approach is mandatory.