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.

PPFIBP1编码 liprin-β1 蛋白，该蛋白已被证明在黑腹果蝇的神经元生长和突触形成中发挥作用。通过外显子组和基因组测序，我们在来自 12 个无关家族的 16 个个体中检测到 9 个极其罕见的纯合子功能丧失变异体。这些个体表现出中度至严重的发育迟缓，通常是难治性早发性癫痫和进行性小头畸形。其他常见的临床表现包括肌肉张力亢进和张力减退、痉挛、发育迟缓和身材矮小、喂养困难、视力受损和先天性心脏缺陷。神经影像学显示大脑形态异常，主要特征为白质脑病、脑室扩大、皮质异常和颅内脑室周围钙化。在颅内钙化的胎儿中，我们发现了一种罕见的纯合错义变体，通过结构分析预测它会扰乱对蛋白质-蛋白质相互作用至关重要的 SAM 结构域区域的拓扑结构。为了进一步了解影响PPFIBP1功能丧失后，我们对秀丽隐杆线虫 PPFIBP1/hlb-1敲除模型进行了自动行为表型分析，该模型揭示了自发和光诱导行为的缺陷，并证实了对乙酰胆碱酯酶抑制剂涕灭威的抗性，表明神经元突触前区存在缺陷。总之，我们将PPFIBP1中的双等位基因功能丧失变异确定为常染色体隐性遗传严重神经发育障碍伴早发性癫痫、小头畸形和脑室周围钙化的原因。