TY - JOUR
T1 - Five new cases of syndromic intellectual disability due to KAT6A mutations
T2 - widening the molecular and clinical spectrum
AU - Urreizti, Roser
AU - Lopez-Martin, Estrella
AU - Martinez-Monseny, Antonio
AU - Pujadas, Montse
AU - Castilla-Vallmanya, Laura
AU - Pérez-Jurado, Luis Alberto
AU - Serrano, Mercedes
AU - Natera-De Benito, Daniel
AU - Martínez-Delgado, Beatriz
AU - Posada-De-La-Paz, Manuel
AU - Alonso, Javier
AU - Marin-Reina, Purificación
AU - O'callaghan, Mar
AU - Grinberg, Daniel
AU - Bermejo-Sánchez, Eva
AU - Balcells, Susanna
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/2/10
Y1 - 2020/2/10
N2 - Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. Conclusions: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.
AB - Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement. Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies. The missense change [p.(Gly359Ser)], also predicted to affect splicing by in silico tools, was functionally tested in the patient's lymphocyte RNA revealing a splicing effect for this allele that would lead to a frameshift and premature truncation. Conclusions: An extensive revision of the clinical features of these five patients revealed high concordance with the 80 cases previously reported, including developmental delay with speech delay, feeding difficulties, hypotonia, a high bulbous nose, and recurrent infections. Other features present in some of these five patients, such as cryptorchidism in males, syndactyly, and trigonocephaly, expand the clinical spectrum of this syndrome.
KW - Clinical characterization
KW - Clinical genetics
KW - KAT6A
KW - Neurodevelopmental disease
KW - Whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85079214316&partnerID=8YFLogxK
U2 - 10.1186/s13023-020-1317-9
DO - 10.1186/s13023-020-1317-9
M3 - Article
C2 - 32041641
AN - SCOPUS:85079214316
SN - 1750-1172
VL - 15
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 44
ER -