Three brothers with a nonsense mutation in KAT6A caused by parental germline mosaicism

Chisei Satoh,Tatsuro Kondoh,Ryuta Maekawa,Mutsuko Miyazaki,Koh-Ichiro Yoshiura,Hiroyuki Mishima,Michiko Doi,Haruo Takahashi,Masafumi Fukuda,Akira Kinoshita

doi:10.1038/hgv.2017.45

Abstract

Mutations in KAT6A, encoding a member of the MYST family of histone acetyl-transferases, were recently reported in patients with a neurodevelopmental disorder (OMIM: #616268, autosomal dominant mental retardation-32). In this report, we describe three siblings with intellectual disability (ID) or global developmental delay and a KAT6A heterozygous nonsense mutation, i.e., c.3070C>T (p.R1024*, ENST00000406337; chr8:41795056G>A on hg19). This mutation was identified by whole-exome sequencing of all three siblings but not in a healthy sibling. The mutation was not detected in the peripheral blood of their parents, suggesting the existence of parental germline mosaicism. The primary symptoms of our patients included severe to profound ID or global developmental delay, including speech delay with craniofacial dysmorphism; these symptoms are consistent with symptoms previously described for patients with KAT6A mutations. Although several features are common among patients with KAT6A mutations, the features are relatively nonspecific, making it difficult to establish a clinical entity based on clinical findings alone. To the best of our knowledge, this is the first report of cases with a KAT6A mutation in an Asian population and these cases represent the first reported instances of germline mosaicism of this disease.

Highlights

Intellectual disability (ID) is defined as an intelligence quotient of 70 or below and affects ~ 1% of children worldwide.[1]
We describe three siblings with ID or global developmental delay with a KAT6A heterozygous nonsense mutation that was potentially transmitted from one of their parents as a germline mosaicism
In this report, we describe three siblings with ID or global developmental delay caused by a KAT6A mutation

Summary

Introduction

Intellectual disability (ID) is defined as an intelligence quotient of 70 or below and affects ~ 1% of children worldwide.[1]. ~ 40% individuals with ID who underwent whole-exome sequencing (WES) or genome sequencing.[3]. WES is a powerful tool in identifying genetic alterations in putative genetic disorders, even those that are undiagnosed, providing a molecular diagnosis rate of 25%.4. For some cases of undiagnosed rare diseases, a new entity has been established among patients whose disorder was previously indistinguishable from other diseases expressing similar phenotypes. Recent studies reported patients with de novo KAT6A mutations among individuals diagnosed with known rare autosomal dominant diseases.[6–8]. Those patients had similar phenotypes, the features were nonspecific. It is difficult to distinguish this disease from other diseases based on clinical findings alone

Methods

Results

Conclusion