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Abstract Genetic diseases affecting the skeletal system present with a wide range of symptoms that make diagnosis and treatment difficult. Genome‐wide association and sequencing studies have identified genes linked to human skeletal diseases. Gene editing of zebrafish models allows researchers to further examine the link between genotype and phenotype, with the long‐term goal of improving diagnosis and treatment. While current automated tools enable rapid and in‐depth phenotyping of the axial skeleton, characterizing the effects of mutations on the craniofacial skeleton has been more challenging. The objective of this study was to evaluate a semi‐automated screening tool can be used to quantify craniofacial variations in zebrafish models using four genes that have been associated with human skeletal diseases (meox1,plod2,sost, andwnt16) as test cases. We used traditional landmarks to ground truth our dataset and pseudolandmarks to quantify variation across the 3D cranial skeleton between the groups (somatic crispant, germline mutant, and control fish). The proposed pipeline identified variation between the crispant or mutant fish and control fish for four genes. Variation in phenotypes parallel human craniofacial symptoms for two of the four genes tested. This study demonstrates the potential as well as the limitations of our pipeline as a screening tool to examine multi‐dimensional phenotypes associated with the zebrafish craniofacial skeleton. 

ABSTRACT Due to the complexity of fish skulls, previous attempts to classify craniofacial phenotypes have relied on qualitative features or sparce 2D landmarks. In this work we aim to identify previously unknown 3D craniofacial phenotypes with a semiautomated pipeline in adult zebrafish mutants. We first estimate a synthetic ‘normative’ zebrafish template using MicroCT scans from a sample pool of wild-type animals using the Advanced Normalization Tools (ANTs). We apply a computational anatomy (CA) approach to quantify the phenotype of zebrafish with disruptions in bmp1a, a gene implicated in later skeletal development and whose human ortholog when disrupted is associated with Osteogenesis Imperfecta. Compared to controls, the bmp1a fish have larger otoliths, larger normalized centroid sizes, and exhibit shape differences concentrated around the operculum, anterior frontal, and posterior parietal bones. Moreover, bmp1a fish differ in the degree of asymmetry. Our CA approach offers a potential pipeline for high-throughput screening of complex fish craniofacial shape to discover novel phenotypes for which traditional landmarks are too sparce to detect. The current pipeline successfully identifies areas of variation in zebrafish mutants, which are an important model system for testing genome to phenome relationships in the study of development, evolution, and human diseases. This article has an associated First Person interview with the first author of the paper.