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A functional assay to classify ZBTB24 missense variants of unknown significance
Author(s) -
Wu Haoyu,
Vonk Kelly K. D.,
Maarel Silvère M.,
Santen Gijs W.E.,
Daxinger Lucia
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23786
Subject(s) - missense mutation , biology , genetics , phenotype , clinical significance , context (archaeology) , computational biology , loss function , gene , genetic testing , pathology , medicine , paleontology
Increasing use of next‐generation sequencing technologies in clinical diagnostics allows large‐scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease‐causing and neutral variants is often hampered by the absence of robust functional tests. Here, we demonstrate that a luciferase reporter assay, in combination with ChIP‐qPCR, reliably separates pathogenic ZBTB24 missense variants in the context of immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome from natural variants in healthy individuals and patients of other diseases. Application of our assay to two published ZBTB24 missense VUSs indicates that they are likely not to cause ICF2 syndrome. Furthermore, we show that rare gnomAD ZBTB24 missense variants in key residues of the C2H2‐ZF domain lead to a loss of function phenotype that resembles ICF2, suggesting that these individuals are carriers of ICF syndrome. In summary, we have developed a robust functional test to validate missense variants in ZBTB24 .