Development and Characterization of a larp7 Knockout Zebrafish Model for Alazami syndrome

Background Alazami syndrome (AS) is a rare autosomal recessive disorder characterized by severe growth restriction, significantly impaired intellectual development, microcephaly, and distinctive facial features, caused by variants in the LARP7 gene. However, the phenotype remains poorly defined due to the limited number of reported cases and the impact of its defects on human health is not yet fully understood. We reported a case with AS, reviewed all previously reported 48 AS patients, and generated a zebrafish knockout of larp gene. Results This patient was compound heterozygous for two pathological variants. Among these AS patients, the main clinical manifestations included intellectual disability (49/49), motor developmental delay (48/48), facial dysmorphism (44/44), short stature (43/47), low weight (29/38), and microcephaly (24/39). More than half also exhibited fetal growth retardation and behavioral abnormalities. These affected individuals all had bi-allelic pathogenic, loss-of-function variants in LARP7. The larp7-/- zebrafish showed reduced body length, smaller eye intervals at 3, 4, and 5 days post-fertilization, delayed hatching and decreased distance and average velocity. Larval locomotion tests indicated impaired activity and response to stimuli, while open field tests revealed elevated anxiety levels. Transcriptome analysis identified increased aberrant splicing events in larp7-/- zebrafish, linked to AS patient phenotypes. Conclusion AS is rare neurodevelopmental delay with severe growth restriction and microcephaly. This study establishes and validates the larp7 konckout zebrafish as an animal model to study AS in vivo, offering a valuable tool for further elucidation of larp7 precise mechanism in the development of this disease and the identification of potential therapeutic targets.