Novel AK-1 gene variants combined with thalassemia causing rare hereditary non-spherocytic hemolytic anemia in a Chinese family.

Adenylate kinase (AK), also referred to as adenosine triphosphate-adenosine monophosphate phosphotransferase, serves an essential function in regulating cellular energy metabolism. A deficiency in red blood cell adenylate kinase 1 (AK-1) is linked to congenital non-spherocytic hemolytic anemia as well as delays in both mental and psychomotor development. This deficiency is an extremely rare autosomal recessive genetic disorder, with 13 highly pathogenic variants of the AK-1 gene documented globally through genetic testing. Thalassemia, a disorder of hemoglobin production, is a common monogenic inherited disease in southern China. Severe forms of thalassemia result in defective hemoglobin synthesis, leading to hemolytic anemia due to the breakdown of red blood cells. A molecular investigation was carried out on a proband with severe hemolytic anemia from a family in Guangxi, China, to identify the underlying cause of the anemia and associated clinical manifestations, offering valuable information for family planning and prenatal counseling. Hematological, biochemical, and thalassemia-specific genetic testing were performed on the proband and family members in relation to chronic hemolytic anemia. Whole-exome sequencing was utilized to detect genetic variants, followed by an analysis of their pathogenic potential. Confirmation was conducted using Sanger sequencing. Prenatal diagnosis was carried out by analyzing amniotic fluid during the mother's second pregnancy. The proband, who presented with severe hemolytic anemia, was diagnosed with the thalassemia genotype- SEA/αα compound βCD41-42/βN. A homozygous mutation, c.464delA (p.Lys155Arg fs*39), was identified in exon 6 of the AK-1 gene. A case of mild thalassemia with severe anemia was investigated, leading to the identification of a novel mutation in the AK-1 gene. Bioinformatics tools predicted the pathogenic nature of this variant, linking it to AK deficiency, which may contribute to the observed severe anemia and associated clinical symptoms.