Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Abstract

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.

Keywords: Clinical characterization; Clinical genetics; KAT6A; Neurodevelopmental disease; Whole exome sequencing.

Fig. 1

Images depicting key phenotypic features of the cases presented here. a Patient 1 facies at 16 years of age, b and c Patient 2 facies at 11 years, d Patient 3 facies at 9 years, e Patient 4 facies at 8 years, and f Patient 5 facies at 6 years. Panels g to k show the patient’s gestalt (at the same age as the facies figure). l Patient 1 hand. m and n Patient 5 ft and hands

Fig. 2

mRNA analysis of mutation c.1075G > A identified in Patient 4. a RT-PCR of KAT6A fragment including exon 5 to 8 in the patient (P), his mother (M) and father (F), and a control sample (C+). b Schematic representation of the normal (upper) and aberrant (lower) splicing of KAT6A exons 5 to 8 and chromatogram of exon 6–8 joining point in the smaller band of the patient. c Chromatograms of the mRNA amplification products in the mother and the patient upper band

Fig. 3

Schematic representation of KAT6A and localization of pathogenic variants, at the protein level (upper panel) and the exonic gene structure (scaled). (1) p.Cys1096Phefs*27; p.Cys1096Leufs*6; p.Cys1096Serfs*6; (2) p.Leu1219Thrfs*75; p.Leu1219Tyrfs*75; (3) p.Gln1348Argfs*7; p.Gln1348*; (4) Mediates interaction with BRPF1, required for histone H3 acetyltransferase activity; (+) activation. In bold, missense mutations. Underlined, mutations identified in the patients presented here