A functional assay to classify ZBTB24 missense variants of unknown significance.

Abstract:

: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.

journal_name

Hum Mutat

journal_title

Human mutation

authors

Wu H,Vonk KKD,van der Maarel SM,Santen GWE,Daxinger L

doi

10.1002/humu.23786

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

1077-1083

issue

8

eissn

1059-7794

issn

1098-1004

journal_volume

40

pub_type

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