TY - JOUR
T1 - De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy
AU - Humbert, Jonathan
AU - Salian, Smrithi
AU - Makrythanasis, Periklis
AU - Lemire, Gabrielle
AU - Rousseau, Justine
AU - Ehresmann, Sophie
AU - Garcia, Thomas
AU - Alasiri, Rami
AU - Bottani, Armand
AU - Hanquinet, Sylviane
AU - Beaver, Erin
AU - Heeley, Jennifer
AU - Smith, Ann C.M.
AU - Berger, Seth I.
AU - Antonarakis, Stylianos E.
AU - Yang, Xiang Jiao
AU - Côté, Jacques
AU - Campeau, Philippe M.
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/9/3
Y1 - 2020/9/3
N2 - KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
AB - KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
KW - KAT5
KW - TIP60
KW - brain malformations
KW - epigenetic
KW - epilepsy
KW - histone
KW - histone acetyltransferase
KW - intellectual disability
KW - sleep disturbance
UR - http://www.scopus.com/inward/record.url?scp=85090005517&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.08.002
DO - 10.1016/j.ajhg.2020.08.002
M3 - Article
C2 - 32822602
AN - SCOPUS:85090005517
SN - 0002-9297
VL - 107
SP - 564
EP - 574
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -