TY - JOUR
T1 - Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles
AU - MKHK Research Consortium
AU - Haghshenas, Sadegheh
AU - Bout, Hidde J
AU - Schijns, Josephine M
AU - Levy, Michael A
AU - Kerkhof, Jennifer
AU - Bhai, Pratibha
AU - McConkey, Haley
AU - Jenkins, Zandra A
AU - Williams, Ella M
AU - Halliday, Benjamin J
AU - Huisman, Sylvia A
AU - Lauffer, Peter
AU - de Waard, Vivian
AU - Witteveen, Laura
AU - Banka, Siddharth
AU - Brady, Angela F
AU - Galazzi, Elena
AU - van Gils, Julien
AU - Hurst, Anna C E
AU - Kaiser, Frank J
AU - Lacombe, Didier
AU - Martinez-Monseny, Antonio F
AU - Fergelot, Patricia
AU - Monteiro, Fabíola P
AU - Parenti, Ilaria
AU - Persani, Luca
AU - Simarro, Fernando Santos
AU - Simpson, Brittany N
AU - Alders, Mariëlle
AU - Robertson, Stephen P
AU - Sadikovic, Bekim
AU - Menke, Leonie A
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/3/28
Y1 - 2024/3/28
N2 - CREB-binding protein (CBP, encoded by CREBBP) and its paralog E1A-associated protein (p300, encoded by EP300) are involved in histone acetylation and transcriptional regulation. Variants that produce a null allele or disrupt the catalytic domain of either protein cause Rubinstein-Taybi syndrome (RSTS), while pathogenic missense and in-frame indel variants in parts of exons 30 and 31 cause phenotypes recently described as Menke-Hennekam syndrome (MKHK). To distinguish MKHK subtypes and define their characteristics, molecular and extended clinical data on 82 individuals (54 unpublished) with variants affecting CBP (n = 71) or p300 (n = 11) (NP_004371.2 residues 1,705–1,875 and NP_001420.2 residues 1,668–1,833, respectively) were summarized. Additionally, genome-wide DNA methylation profiles were assessed in DNA extracted from whole peripheral blood from 54 individuals. Most variants clustered closely around the zinc-binding residues of two zinc-finger domains (ZZ and TAZ2) and within the first α helix of the fourth intrinsically disordered linker (ID4) of CBP/p300. Domain-specific methylation profiles were discerned for the ZZ domain in CBP/p300 (found in nine out of 10 tested individuals) and TAZ2 domain in CBP (in 14 out of 20), while a domain-specific diagnostic episignature was refined for the ID4 domain in CBP/p300 (in 21 out of 21). Phenotypes including intellectual disability of varying degree and distinct physical features were defined for each of the regions. These findings demonstrate existence of at least three MKHK subtypes, which are domain specific (MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4) rather than gene specific (CREBBP/EP300). DNA methylation episignatures enable stratification of molecular pathophysiologic entities within a gene or across a family of paralogous genes.
AB - CREB-binding protein (CBP, encoded by CREBBP) and its paralog E1A-associated protein (p300, encoded by EP300) are involved in histone acetylation and transcriptional regulation. Variants that produce a null allele or disrupt the catalytic domain of either protein cause Rubinstein-Taybi syndrome (RSTS), while pathogenic missense and in-frame indel variants in parts of exons 30 and 31 cause phenotypes recently described as Menke-Hennekam syndrome (MKHK). To distinguish MKHK subtypes and define their characteristics, molecular and extended clinical data on 82 individuals (54 unpublished) with variants affecting CBP (n = 71) or p300 (n = 11) (NP_004371.2 residues 1,705–1,875 and NP_001420.2 residues 1,668–1,833, respectively) were summarized. Additionally, genome-wide DNA methylation profiles were assessed in DNA extracted from whole peripheral blood from 54 individuals. Most variants clustered closely around the zinc-binding residues of two zinc-finger domains (ZZ and TAZ2) and within the first α helix of the fourth intrinsically disordered linker (ID4) of CBP/p300. Domain-specific methylation profiles were discerned for the ZZ domain in CBP/p300 (found in nine out of 10 tested individuals) and TAZ2 domain in CBP (in 14 out of 20), while a domain-specific diagnostic episignature was refined for the ID4 domain in CBP/p300 (in 21 out of 21). Phenotypes including intellectual disability of varying degree and distinct physical features were defined for each of the regions. These findings demonstrate existence of at least three MKHK subtypes, which are domain specific (MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4) rather than gene specific (CREBBP/EP300). DNA methylation episignatures enable stratification of molecular pathophysiologic entities within a gene or across a family of paralogous genes.
KW - CREB-binding protein
KW - DNA methylation
KW - E1A-associated protein p300
KW - MKHK
KW - Menke-Hennekam syndrome
KW - Rubinstein-Taybi syndrome
KW - episignatures
KW - intellectual disability
KW - intrinsically disordered linker
KW - zinc-finger domain
UR - http://www.scopus.com/inward/record.url?scp=85190349831&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2024.100287
DO - 10.1016/j.xhgg.2024.100287
M3 - Article
C2 - 38553851
SN - 2666-2477
VL - 5
SP - 100287
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100287
ER -