Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder

Abstract

Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc.

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

“…Since 2015, around 80 cases of syndromic intellectual disability due to mutations at the KAT6A gene have been described in the literature, delineating a new syndrome with variable presentation ( Table 2 and Fig. 3) [4][5][6][7][8][9][10][11][12][13][14][15]. Here, we present 5 patients with de novo variants at KAT6A, four 'late truncating' and one missense variant, and we describe their clinical presentations, adding further clinical and molecular delineation to the KAT6A syndrome.…”

“…32; MIM # 616268). To date, a total of 79 patients have been reported [4][5][6][7][8][9][10][11][12][13][14][15]. All of them present with developmental delay (DD) or intellectual disability (ID) with speech delay.…”

ZNF341 controls STAT3 expression and thereby immunocompetence

“…In this regard, KAT6A , the gene whose promoter has the second top-binding site by ChIP, was down-regulated in our transcriptome analysis (table S3). Interestingly, mutations in KAT6A were recently identified in patients presenting with neurodevelopmental disorders (47). Lower KAT6A expression may contribute to the intellectual disabilities observed in our patients.…”

Variants in KAT6A and pituitary anomalies

“…With great interest we have read the article by Millan et al [] describing six patients with pathogenic de novo variants in KAT6A . The patients shared a common phenotype of moderate to severe neurodevelopmental delay, severe speech delay, hypotonia, and a characteristic face.…”

“…PSIS belongs to the spectrum of midline brain abnormalities and is often associated with other extra‐pituitary midline malformations (Reynaud et al, ). Thus, far 17 patients with dominantly acting mutations in KAT6A have been described, and in all affected individuals the phenotype consisted of neurodevelopmental and speech delay, and a typical facial morphology (Arboleda et al, ; Millan et al, ; Tham et al, ). Brain MRI studies were reported in 16 of these children, and demonstrated subtle midline brain abnormalities in three: one had a missing olfactory bulb (Millan et al, ), and two had a cavum of the septum pellucidum (Tham et al, ).…”