Abstract
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.
Highlights
Variant effect prediction remains a challenge in medical genomics [1, 2]
The problem can be acute for disorders where a substantial number of genes are mutable to overlapping phenotypes, including ciliopathies such as Joubert syndrome and related disorders (JSRD)
Targets were selected to include a range of predicted effects in commonly used variant effect algorithms (Table 1) and to include a range of allele frequencies in databases depleted for close relatives and patients with Mendelian disorders [3, 4]
Summary
Variant effect prediction remains a challenge in medical genomics [1, 2]. Progress from large reference databases such as ExAC [3], gnomAD [4], and UK Biobank [5] allows powerful statistical evidence against pathogenicity, based on allele frequency [6] for rare variants that had appeared unique to patients in smaller samples. Attempts to model prediction accuracy can suffer where ground truth is not available and clinical variant databases in current use include assertions often based on limited evidence. ZNF423 mutations have been reported as pathogenic in JSRD patients [7] and other neurodevelopmental disorders [8], but most patient variants have uncertain significance and even those asserted pathogenic in public databases rely on very limited data. This is true for many rare disorders
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
