Discovery and analysis of a novel mutation (G774E) in the Lysine Demethylase 6A (KDM6A) gene causing congenital heart disease with various neurodevelopmental disorders

Mahmood Rasool, Majed Alsulami, Ayat Mohammed Shorbaji, Absarul Haque, Loubna Siraj Mira, Mohammad Basabrain, Sherin Bakhashab, Mohamed Nabil Alama, Sajjad Karim, Isam M Abu Zeid, Hisham N Altayb, Peter Natesan Pushparaj

Abstract


Background: Congenital heart defects (CHD) are the most common birth defects, affecting approximately 0.8% of live births worldwide. CHD impairs the function and structure of the heart and blood vessels. Due to this damage, blood flow is impaired, which affects many major organs, including the brain, and causes various neurodevelopmental disorders.

Methods: In this study, we recruited a five-generation pedigree for analysis. The proband was born with congenital heart disease and subsequently developed various neurodevelopmental disorders. To understand the causes of the disease, we performed clinical whole-exome sequencing and applied various bioinformatics tools to determine the pathogenicity of the mutation.

Results: Molecular investigation revealed a novel lethal mutation (c.2321G>A) in KDM6A, causing the substitution of Glycine to Glutamic acid (Gly774Glu). The mutation was further confirmed using Sanger sequencing. Various bioinformatics tools were used to predict the lethality of the mutations. KDM6A disruption causes various diseases, among which Kabuki syndrome is the most prevalent.

Conclusion: Our findings may aid in the further development of genome-based medicines, leading to a reduction in mortality rates and improved healthcare in newborns.

Keywords:

Congenital heart disease, Kabuki syndrome, Neurodevelopmental disorder, Whole exome sequencing, Novel mutation

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References


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DOI: https://doi.org/10.62940/als.v13i1.3977

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