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Introduction: The underlying molecular defects of congenital hydrocephalus are heterogeneous and many isolated forms of hydrocephalus remain unsolved at the molecular level. Congenital hydrocephalus in males associated with agenesis of the corpus callosum is a notable characteristic of L1CAM gene which is by far the most common genetic etiology of congenital hydrocephalus. Methods and Results: Sequencing of the L1CAM gene on 25 male patients/fetuses who had been presented with hydrocephalus revealed 6 patients and two fetuses with different hemizygous pathogenic variants. Our study identified 4 novel variants and 4 previously reported. The detection rate was 32%, and all the variants were shown to be maternally inherited. Nonsense variants were detected in 3 patients, while missense variants were detected in 2 patients. Frameshift, silent, and splicing variant, each was detected in 1 patient. The clinical manifestations of the patients are in line with those frequently observed including communicating hydrocephalus and agenesis of the corpus callosum. Moreover, rippled ventricles with subdural collection and asymmetry of ventricles after shunt operation were seen in 1 patient and 2 patients, respectively. In addition, abnormal basal ganglia were found in 4 patients which seems to be an additional distinct new finding. We also describe a patient with novel nonsense variant with the rare association of Hirschsprung’s disease. This patient displayed additionally multiple porencephalic cysts and encephalomalacia secondary to hemorrhage due to repeated infections after shunt operation. The patients with the missense variants showed long survival, while those with truncating variants showed poor prognosis. Conclusion: This report adds knowledge of novel pathogenic variants to the L1CAM variant database. Furthermore, we evaluated the clinical and imaging data of these patients.

Introduction: Pathogenic variants in the PIEZO family member 2 (PIEZO2) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic PIEZO2 variants have been reported to show posterior fossa anomalies. Methods and Results: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in PIEZO2. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of PIEZO2 variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. Conclusion: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous PIEZO2-related disorders represent a continuum with overlapping phenotypic features.

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. CC BY 4.0© 2022 The AuthorsCorrespondence: andre.brown@lms.mrc.ac.uk (A.E.X.B.), konrad.platzer@medizin.uni-leipzig.de (K.P.)We thank all families that participated in this study. This project has received funding from the European Research Council under the European External Action Service Horizon 2020 Research and Innovation Program (grant agreement no. 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. H.T. was supported by the European External Action Service Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 608473.