Clinical and Genetic Functional Validation of a Novel <i>AP1S1</i> Mutation Causing MEDNIK Syndrome

<b>Background:</b> MEDNIK syndrome is a rare copper metabolism disorder caused by <i>AP1S1</i> variants. Herein, we report the clinical and genetic characteristics of MEDNIK syndrome in two siblings. <b>Methods:</b> The clinical treatment process for MEDNIK syndrome and over 4 years of follow-up data were analysed in two siblings. Microscopic observations of the patients' hair were conducted. Gene sequencing, three-dimensional structural reconstruction of protein sequences, and in vitro mRNA splicing experiments were performed. <b>Results:</b> The proband and his sister exhibited developmental delays, seizures, yellow hair, sparse teeth and a high forehead. Furthermore, the sister initially presented with intractable diarrhoea and severe pneumonia. Both siblings showed varying degrees of developmental delays during follow-up, and the proband also showed symptoms of attention deficit hyperactivity disorder. The microscopic hair examination revealed a deficiency in intermediate pigment, a pale colour and an intermittent or absent medulla. Genetic sequencing revealed a homozygous <i>AP1S1</i> mutation at the splicing site (NM_001283.3): c.430-1G>A. The in vitro mRNA splicing experiments confirmed a single base-pair deletion in the fifth exon of the mRNA sequence of the mutated plasmid, resulting in a frameshift mutation (p.Glu144ArgfsTer83). The mutation was inherited from both parents and classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines, based on clinical features and family analysis. <b>Conclusion:</b> Both children with MEDNIK syndrome exhibited heterogeneous clinical phenotypes. Sparse teeth may be a previously unnoticed feature of MEDNIK syndrome. The pathogenic c.430-1G>A homozygous variant enriches the mutation spectrum of <i>AP1S1</i>. This mutation causes a frameshift mutation in the protein, altering the protein structure and affecting protein function.