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

• Published in: PLoS genetics Vol. 16; no. 9; p. e1009017
• Main Authors: Deshpande, Ojas, Lara, Raquel Z, Zhang, Oliver R, Concepcion, Dorothy, Hamilton, Bruce A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.09.2020; Public Library of Science (PLoS)
• Subjects: Algorithms; Alleles; Amino acids; Anatomy; Animals; Biology and Life Sciences; Brain - pathology; Brain abnormalities; Brain architecture; Brain Diseases - genetics; Cancer; Disease Models, Animal; Female; Gene Frequency - genetics; Genetic aspects; Genetic variation; Genomics; Health aspects; Humans; Intolerance; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Moores, John; Mutation; Nervous System Malformations - genetics; Neural Tube Defects - genetics; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Nonsense mutation; Patients; Physiological aspects; Proteins; Proteins - genetics; Proteins - metabolism; Research and Analysis Methods; Transcription; Transcription Factors - genetics; Zinc finger proteins; Zinc Fingers; United States; La Jolla California; United States > US
• DOI: 10.1371/journal.pgen.1009017
• ISSN: 1553-7404; 1553-7390

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.