A New Unc45a 5'utr Variant In Patients With Aagenaes Syndrome

Aagenaes syndrome, also known as lymphoedema cholestasis syndrome 1 (LCS1), is a rare autosomal recessive disorder characterized by neonatal cholestasis and chronic lymphedema, primarily affecting the lower extremities. The genetic basis for this syndrome was recently linked to a variant in the 5'-untranslated region (5'-UTR) of the UNC45A gene, located on chromosome 15q. This study aimed to identify the genetic mutations associated with Aagenaes syndrome in two siblings and to explore their clinical implications. Whole-exome sequencing (WES) was conducted on two siblings with neonatal cholestasis and lymphedema. WES identified a single base pair change in the 5'-untranslated region (5'-UTR) of the UNC45A gene (c.-88G>A) in both siblings. Additionally, both were heterozygous for an exonic loss-of-function variant (c.1591C>T; p.Arg531Ter) in UNC45A. Clinically, both siblings presented with neonatal cholestasis and lymphedema; however, one sibling developed severe liver failure, requiring a liver transplant. Despite carrying the same variants, the clinical outcomes differed between the two patients. The identification of a novel 5'-UTR variant (c.-88G>A), along with an exonic variant in UNC45A, expands the genetic and clinical understanding of Aagenaes syndrome. This study confirms the involvement of the 5'-UTR region of UNC45A in the disease pathogenesis, while demonstrating that Aagenaes syndrome is not exclusively associated with the previously reported c.-98G>T variant found in Norwegian cases. These findings underscore the importance of genetic screening for accurate diagnosis and management of Aagenaes syndrome and provide new insights into the critical regulatory role of the 5'-UTR in disease development. Further research is needed to elucidate the mechanisms underlying phenotypic variability in this rare disorder. Evaluation of mRNA and protein levels would have been valuable to better understand the functional effects of these variants; however, due to current resource constraints, such studies could not be conducted.