Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
Erik Rosenhahn, Thomas O’Brien, Maha S. Zaki, Ina Sorge, Dagmar Wieczorek, Kevin Rostásy, Antonio Vitobello, Sophie Nambot, Fowzan S. Alkuraya, Mais O. Hashem, Amal Alhashem, Brahim Tabarki, Abdullah Alamri, Ayat H. Al Safar, Dalal Bubshait, Nada F. Alahmady, Joseph G. Gleeson, Mohamed S. Abdel‐Hamid, Nicole Lesko, Sofia Ygberg, Sandrina P. Correia, Anna Wredenberg, Shahryar Alavi, Seyed Mohammad Seyedhassani, Mahya Ebrahimi Nasab, Haytham Hussien, Tarek Omar, Inès Harzallah, Renaud Touraine, Homa Tajsharghi, Heba Morsy, Henry Houlden, Mohammad Shahrooei, Maryam Ghavideldarestani, Ghada M. H. Abdel‐Salam, Annalaura Torella, Mariateresa Zanobio, Gaetano Terrone, Nicola Brunetti‐Pierri, Abdolmajid Omrani, Julia Hentschel, Johannes R. Lemke, Heinrich Sticht, Rami Abou Jamra, André EX Brown, Reza Maroofian, Konrad Platzer
Abstract
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.