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Three brothers with a nonsense mutation in KAT6A caused by parental germline mosaicism
Chisei Satoh1,2, Ryuta Maekawa2, Akira Kinoshita2
11Department of Otolaryngology-Head and Neck Surgery, Unit of Translation Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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.
Insights
This study identifies a new KAT6A gene mutation in three siblings with intellectual disability, suggesting parental germline mosaicism. This research is the first to report KAT6A mutations in an Asian population.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Mutations in the KAT6A gene, encoding a histone acetyl-transferase, are linked to neurodevelopmental disorders.
- Previous studies have identified KAT6A mutations in affected individuals, but clinical features can be nonspecific.
Purpose of the Study:
- To report three siblings with intellectual disability and a novel KAT6A mutation.
- To investigate the potential for parental germline mosaicism in KAT6A-related disorders.
- To contribute to the understanding of KAT6A mutations in a non-European population.
Main Methods:
- Whole-exome sequencing was performed on three affected siblings and one healthy sibling.
- Parental peripheral blood DNA was analyzed to assess for mosaicism.
- Clinical features of the affected individuals were documented and compared to existing literature.
Main Results:
- A heterozygous nonsense mutation in KAT6A (c.3070C>T) was identified in all three affected siblings.
- The mutation was absent in the healthy sibling and not detected in parental blood, indicating germline mosaicism.
- Patients presented with severe intellectual disability, global developmental delay, speech delay, and craniofacial dysmorphism.
Conclusions:
- This study reports the first cases of KAT6A mutation in an Asian population.
- The findings suggest parental germline mosaicism as a potential mechanism for transmitting KAT6A mutations.
- Further research is needed to delineate the specific clinical spectrum of KAT6A-related neurodevelopmental disorders.
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