Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum
Por:
Urreizti R, Lopez-Martin E, Martinez-Monseny T, Pujadas M, Castilla-Vallmanya L, Pérez-Jurado LA, Serrano M, Natera-de Benito D, Martínez-Delgado B, Posada-de-la-Paz M, Alonso J, Marin-Reina P, O'Callaghan-Gordo M, Grinberg-Vaisman DR, Bermejo-Sánchez E and Balcells S
Publicada:
10 feb 2020
Ahead of Print:
10 feb 2020
Resumen:
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.
Filiaciones:
Urreizti R:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain.
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Present address: Neurometabolic Unit, Hospital Sant Joan de Déu, Barcelona, Spain.
Lopez-Martin E:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Martinez-Monseny T:
Department of Genetic and Molecular Medicine and Pediatric Rare Diseases Institute (IPER), Institut de Recerca Sant Joan de Déu (IRSJD), Hospital Sant Joan de Déu, Barcelona, Spain
Pujadas M:
Genetics Unit, University Pompeu Fabra, Hospital del Mar Research Institute IMIM, Barcelona, Spain
Castilla-Vallmanya L:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Pérez-Jurado LA:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Genetics Unit, University Pompeu Fabra, Hospital del Mar Research Institute IMIM, Barcelona, Spain
Women's and Children's Hospital, South Australian Health and Medical Research Institute and The University of Adelaide, Adelaide, Australia
Serrano M:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Natera-de Benito D:
Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Martínez-Delgado B:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Posada-de-la-Paz M:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Alonso J:
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Marin-Reina P:
Dysmorpholgy and Clinical Genetics, Division of Neonatology, Neonatal Research Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
O'Callaghan-Gordo M:
Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Grinberg-Vaisman DR:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Bermejo-Sánchez E:
Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Balcells S:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, Barcelona, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Green Published, Green Submitted, gold
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