Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile

Introduction Kondo-Fu syndrome is an ultra-rare genetic disorder caused by variants in the MBTPS1 gene, which plays a key role in lysosomal function and skeletal homeostasis. Clinical presentation is characterized by spondyloepiphyseal dysplasia, low bone mineral density, and cataracts. This study aimed to expand the clinical spectrum by describing distinctive phenotypic features and highlighting novel genetic findings and biochemical alterations relevant to bone metabolism. Methods We conducted extensive clinical, radiological (X-ray, 3D-CT scan, MRI), biochemical, and genetic investigations in a patient with Kondo-Fu syndrome in whom initial diagnostic evaluation was inconclusive. Whole-exome sequencing was performed on the proband, and the candidate variant was validated by Sanger sequencing in the family. We further evaluated its functional impact using real-time PCR, compared to two healthy donors. Results Clinical investigations revealed the characteristic clinical features of Kondo-Fu syndrome, including osteopenia, spondyloepiphyseal dysplasia, cataracts, and intellectual disability. Furthermore, the patient presented previously unreported rare congenital anomalies, including os odontoideum, split atlas, and diaphragmatic hernia. Biochemical analysis revealed elevated alkaline phosphatase levels and decreased high-density lipoprotein and vitamin D levels, which could be associated with osteopenia and suggest altered bone and mineral metabolism. Genetic investigation revealed a novel homozygous variant, c.963 + 2T>A, in MBTPS1 , leading to the diagnosis of Kondo-Fu syndrome, which was consistent with the patient’s clinical manifestations. Gene expression analysis demonstrated the under expression of MBTPS1 , highlighting the deleterious effect of this variant. Conclusions This study identifies a novel variant underlying Kondo-Fu syndrome and reveals previously unreported phenotypic features alongside exploratory biochemical findings that may provide preliminary insights into altered bone and mineral metabolism.