Table 3.
Genotypes, methylation profiles/episignatures, and ACMG criteria for the variants in CREBBP (GenBank: NM_004380.2) or EP300 (GenBank: NM_001429.3)
| Gene | Domain | DNA variant | Predicted protein change | Inheritance | Episignature | ACMG before DNA methylation | ACMG after DNA methylation | |
|---|---|---|---|---|---|---|---|---|
| C.Z.1 | CREBBP | ZZ | c.5128T>C | p.(Cys1710Arg) | de novo | N/A | likely pathogenic | – |
| C.Z.2 | CREBBP | ZZ | c.5128T>A | p.(Cys1710Ser) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.3 | CREBBP | ZZ | c.5128T>C | p.(Cys1710Arg) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.4 | CREBBP | ZZ | c.5129G>A | p.(Cys1710Tyr) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.5 | CREBBP | ZZ | c.5155C>G | p.(His1719Asp) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.6 | CREBBP | ZZ | c.5170G>A | p.(Glu1724Lys) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.7 | CREBBP | ZZ | c.5186G>A | p.(Cys1729Tyr) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.Z.8 | CREBBP | ZZ | c.5210G>A | p.(Ser1737Asn) | unknown | None | VUS | – |
| C.Z.9 | CREBBP | ZZ | c.5212C>A | p.(His1738Asn) | unknown | N/A | VUS | – |
| C.Z.10 | CREBBP | ZZ | c.5219A>G | p.(His1740Arg) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| E.Z.3 | EP300 | ZZ | c.5009G>A | p.(Cys1670Tyr) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| E.Z.1 | EP300 | ZZ | c.5074T>C | p.(Cys1692Arg) | de novo | N/A | likely pathogenic | – |
| E.Z.2 | EP300 | ZZ | c.5074T>G | p.(Cys1692Gly) | de novo | MKHK_ZZ | likely pathogenic | pathogenic |
| C.ZT.1 | CREBBP | In between ZZ and TAZ2 | c.5237G>T | p.(Gly1746Val) | de novo | MKHK_ID4 | VUS | likely pathogenic |
| C.ZT.2 | CREBBP | In between ZZ and TAZ2 | c.5240T>G | p.(Leu1747Arg) | de novo | Moderate MKHK_ID4 | VUS | likely pathogenic |
| C.T.1 | CREBBP | TAZ2 | c.5323T>C | p.(Cys1775Arg) | maternally inherited | None | likely pathogenic | – |
| C.T.2 | CREBBP | TAZ2 | c.5323T>C | p.(Cys1775Arg) | de novo | None | likely pathogenic | – |
| C.T.3 | CREBBP | TAZ2 | c.5336T>C | p.(Leu1779Pro) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.4 | CREBBP | TAZ2 | c.5345C>T | p.(Ala1782Val) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.5 | CREBBP | TAZ2 | c.5345C>T | p.(Ala1782Val) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.6 | CREBBP | TAZ2 | c.5354G>A | p.(Cys1785Tyr) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.8 | CREBBP | TAZ2 | c.5357G>A | p.(Arg1786His) | de novo | None | likely pathogenic | – |
| C.T.9 | CREBBP | TAZ2 | c.5357G>A | p.(Arg1786His) | de novo | N/A | likely pathogenic | – |
| C.T.7a | CREBBP | TAZ2 | c.5357G>C | p.(Arg1786Pro) | de novo | None | likely pathogenic | – |
| C.T.10 | CREBBP | TAZ2 | c.5357G>C | p.(Arg1786Pro) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.11 | CREBBP | TAZ2 | c.5362G>A | p.(Ala1788Thr) | de novo | N/A | pathogenic | – |
| C.T.12b | CREBBP | TAZ2 | c.5362G>A | p.(Ala1788Thr) | de novo | MKHK_TAZ2 | pathogenic | pathogenic |
| C.T.13b | CREBBP | TAZ2 | c.5362G>A | p.(Ala1788Thr) | de novo | MKHK_TAZ2 | pathogenic | pathogenic |
| C.T.14 | CREBBP | TAZ2 | c.5366A>C | p.(Asn1789Thr) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.15 | CREBBP | TAZ2 | c.5367C>G | p.(Asn1789Lys) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.16 | CREBBP | TAZ2 | c.5456G>A | p.(Cys1819Tyr) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.17 | CREBBP | TAZ2 | c.5456G>T | p.(Cys1819Phe) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.18 | CREBBP | TAZ2 | c.5462A>G | p.(Gln1821Arg) | de novo | None | likely pathogenic | – |
| C.T.19 | CREBBP | TAZ2 | c.5478C>G | p.(Cys1826Trp) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.30 | CREBBP | TAZ2 | c.5482_5484del | p.(Tyr1828del) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.20 | CREBBP | TAZ2 | c.5485C>G | p.(His1829Asp) | de novo | N/A | likely pathogenic | – |
| C.T.21 | CREBBP | TAZ2 | c.5513G>A | p.(Cys1838Tyr) | de novo | MKHK_TAZ2 | likely pathogenic | pathogenic |
| C.T.22b | CREBBP | TAZ2 | c.5518G>A | p.(Val1840Met) | paternally inherited | N/A | VUS | – |
| C.T.23b | CREBBP | TAZ2 | c.5518G>A | p.(Val1840Met) | unknown | N/A | VUS | – |
| C.T.24b | CREBBP | TAZ2 | c.5518G>A | p.(Val1840Met) | paternally inherited | N/A | VUS | – |
| C.T.25a | CREBBP | TAZ2 | c.5518_5544del | p.(Val1840_His1848del) | de novo | None | likely pathogenic | – |
| E.T.1 | EP300 | TAZ2 | c.5245C>T | p.(Arg1749Trp) | de novo | N/A | likely pathogenic | – |
| C.TI.29a | CREBBP | in between TAZ2 and ID4 | c.5552G>A | p.(Arg1851His) | de novo | none | VUS | – |
| C.I.3b | CREBBP | ID4 | c.5555_5575del | p.(Gln1852_Arg1858del) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.4b | CREBBP | ID4 | c.5555_5575del | p.(Gln1852_Arg1858del) | de novo | N/A | pathogenic | – |
| C.I.5b | CREBBP | ID4 | c.5555_5575del | p.(Gln1852_Arg1858del) | de novo | N/A | pathogenic | – |
| C.I.6 | CREBBP | ID4 | c.5561A>C | p.(Gln1854Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| C.I.7 | CREBBP | ID4 | c.5563_5583dup | p.(Ile1855_Gln1861dup) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| C.I.8 | CREBBP | ID4 | c.5576T>C | p.(Leu1859Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| C.I.9 | CREBBP | ID4 | c.5595_5597del | p.(Met1865_Arg1866delinsIle) | de novo | N/A | likely pathogenic | – |
| C.I.10 | CREBBP | ID4 | c.5599C>T | p.(Arg1867Trp) | de novo | N/A | likely pathogenic | – |
| C.I.11 | CREBBP | ID4 | c.5600G>A | p.(Arg1867Gln) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| C.I.12a | CREBBP | ID4 | c.5600G>A | p.(Arg1867Gln) | de novo | N/A | likely pathogenic | – |
| C.I.13a | CREBBP | ID4 | c.5600G>A | p.(Arg1867Gln) | unknown | N/A | likely pathogenic | – |
| C.I.14 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.15 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.16 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.17 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.18 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.19 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.20 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.21 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.22 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | unknown | N/A | pathogenic | – |
| C.I.23 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.24 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.25 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.26 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.34 | CREBBP | ID4 | c.5602C>T | p.(Arg1868Trp) | de novo | N/A | pathogenic | – |
| C.I.27 | CREBBP | ID4 | c.5603G>A | p.(Arg1868Gln) | de novo | N/A | pathogenic | – |
| C.I.28 | CREBBP | ID4 | c.5603G>A | p.(Arg1868Gln) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.29 | CREBBP | ID4 | c.5608G>C | p.(Ala1870Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| C.I.30 | CREBBP | ID4 | c.5614A>G | p.(Met1872Val) | de novo | MKHK_ID4 | pathogenic | pathogenic |
| C.I.31 | CREBBP | ID4 | c.5614A>G | p.(Met1872Val) | de novo | N/A | pathogenic | – |
| C.I.32 | CREBBP | ID4 | c.5614A>G | p.(Met1872Val) | de novo | N/A | pathogenic | – |
| C.I.33 | CREBBP | ID4 | c.5615T>G | p.(Met1872Arg) | de novo | N/A | likely pathogenic | – |
| E.I.1 | EP300 | ID4 | c.5471A>C | p.(Gln1824Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| E.I.2 | EP300 | ID4 | c.5483T>C | p.(Leu1828Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| E.I.3 | EP300 | ID4 | c.5486G>C | p.(Arg1829Pro) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| E.I.5 | EP300 | ID4 | c.5492_5494del | p.(Arg1831del) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| E.I.4 | EP300 | ID4 | c.5492_5495delinsTGGC | p.(Arg1831_Met1832delinsMetAla) | unknown | MKHK_ID4 | VUS | likely pathogenic |
| E.I.6 | EP300 | ID4 | c.5492G>C | p.(Arg1831Thr) | de novo | MKHK_ID4 | likely pathogenic | pathogenic |
| E.I.7 | EP300 | ID4 | c.5492G>C | p.(Arg1831Thr) | unknown | MKHK_ID4 | likely pathogenic | pathogenic |
N/A, not applicable; VUS, variant of uncertain significance.
a
Additional variants were found in the following individuals: C.T.7, CREBBP (NM_004380.2): c.7105C>A, p.(Pro2369Thr), de novo, VUS; C.T.25, GRCh37: del10q21.3 65.73-66.26 Mb (containing no genes), maternally inherited, VUS; C.TI.29, MED12 (NM_005120.3), p.(Gly2141Glu), maternally inherited, VUS; C.I.12, GRCh 37: del6p12.3 392 kb (including RUNX2), de novo, pathogenic; and C.I.13, GRCh 37: dup9q34.3 (140,722,407-141,020,389)x3 (including CACNA1B & EHMT1), inheritance unknown, VUS.
b
C.T.12 and C.T.13 are siblings; C.T.22 and C.T.24 are siblings and children of C.T.23, who is their father; C.I.3, C.I.4, and C.I.5 are siblings.