ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities

Autoři: Ojas Deshpande aff001;  Raquel Z. Lara aff001;  Oliver R. Zhang aff001;  Dorothy Concepcion aff001;  Bruce A. Hamilton aff001
Působiště autorů: Department of Cellular and Molecular Medicine, Institute for Genomic Medicine, Rebecca and John Moores UCSD Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, United States of America aff001;  Department of Medicine, Institute for Genomic Medicine, Rebecca and John Moores UCSD Cancer Center, University of California, San Diego School of Medicine, Gilman Drive, La Jolla, CA, United States of America aff002
Vyšlo v časopise: ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009017
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009017


Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.

Klíčová slova:

Alleles – Cerebellum – Deletion mutation – Heterozygosity – Homozygosity – Mouse models – Substitution mutation – corpus callosum


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