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Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
Institute of Human Genetics, University of Leipzig Medical Center, Germany.
MRC London Institute of Medical Sciences, United Kingdom.
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Department of Pediatric Radiology, University Hospital Leipzig, Germany.
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2022 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, no 8, p. 1421-1435Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
Cell Press , 2022. Vol. 109, no 8, p. 1421-1435
Keywords [en]
Acetylcholinesterase, Animals, Drosophila melanogaster, Epilepsy, Loss of Heterozygosity, Microcephaly, Nervous System Malformations, Neurodevelopmental Disorders, Pedigree, animal, genetics, heterozygosity loss, mental disease, nervous system malformation
National Category
Medical Genetics Clinical Laboratory Medicine Neurology Biomedical Laboratory Science/Technology Cell and Molecular Biology
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-21694DOI: 10.1016/j.ajhg.2022.06.008ISI: 000850681500006PubMedID: 35830857Scopus ID: 2-s2.0-85135598374OAI: oai:DiVA.org:his-21694DiVA, id: diva2:1688208
Funder
EU, European Research Council, 714853
Note

CC BY 4.0

© 2022 The Authors

Correspondence: 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.

Available from: 2022-08-18 Created: 2022-08-18 Last updated: 2022-10-17Bibliographically approved

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Tajsharghi, Homa

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