Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

Rosenhahn E, O'Brien TJ, Zaki MS, Sorge I, Wieczorek D, Rostasy K, Vitobello A, Nambot S, Alkuraya FS, Hashem MO, Alhashem A, Tabarki B, Alamri AS, Al Safar AH, Bubshait DK, Alahmady NF, Gleeson JG, Abdel-Hamid MS, Lesko N, Ygberg S, Correia SP, Wredenberg A, Alavi S, Seyedhassani SM, Ebrahimi Nasab M, Hussien H, Omar TE, Harzallah I, Touraine R, Tajsharghi H, Morsy H, Houlden H, Shahrooei M, Ghavideldarestani M, Abdel-Salam GM, Torella A, Zanobio M, Terrone G, Brunetti-Pierri N, Omrani A, Hentschel J, Lemke JR, Sticht H, Abou Jamra R, Brown AE, Maroofian R, Platzer K (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 109

Pages Range: 1421-1435

Journal Issue: 8

DOI: 10.1016/j.ajhg.2022.06.008

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.

Authors with CRIS profile

Involved external institutions

Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) Imam Abdulrahman Bin Faisal University Saudi Arabia (SA) Riyadh Armed Forces Hospital Saudi Arabia (SA) Medical Research Council United Kingdom (GB) King Faisal Specialist Hospital & Research Centre Saudi Arabia (SA) National Research Centre (NRC) / المركز القومي للبحوث Egypt (EG) Universität Leipzig Germany (DE) Alfaisal University Saudi Arabia (SA) University College London (UCL) United Kingdom (GB) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Université Bourgogne Franche-Comté France (FR) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universität Witten/Herdecke Germany (DE) Università degli Studi di Napoli Federico II Italy (IT) Alexandria University / جامعة الإسكندرية‎‎ Egypt (EG) University of Isfahan (UI) / Esfahan University / دانشگاه اصفهان Iran, Islamic Republic of (IR) Universitätsklinikum Düsseldorf Germany (DE) Karolinska Institute Sweden (SE) Centre Hospitalier Universitaire de Saint-Étienne (CHU) France (FR) Bushehr University of Medical Sciences (BPUMS) / دانشگاه علوم پزشکی بوشهر Iran, Islamic Republic of (IR) Università degli studi della Campania Luigi Vanvitelli Italy (IT) Universitätsklinikum Leipzig Germany (DE) University of Skövde / Högskolan i Skövde (HIS) Sweden (SE)

How to cite

APA:

Rosenhahn, E., O'Brien, T.J., Zaki, M.S., Sorge, I., Wieczorek, D., Rostasy, K.,... Platzer, K. (2022). Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications. American Journal of Human Genetics, 109(8), 1421-1435. https://doi.org/10.1016/j.ajhg.2022.06.008

MLA:

Rosenhahn, Erik, et al. "Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications." American Journal of Human Genetics 109.8 (2022): 1421-1435.

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