Loeys-Dietz syndrome associated with truncating variants in PMEPA1 gene: First description of the phenotypic spectrum in three Belgian families

PMEPA1 has recently been identified as a predisposition gene for familial thoracic aortic aneurysm disease (FTAAD) related to Loeys-Dietz syndrome (LDS). The PMEPA1 gene product is involved in the transforming growth factor beta (TGFβ) pathway and acts as an inhibitor of this pathway. A gain-of-function is hypothesized to be the disease-causing mechanism.
We report the genotype and phenotype of seven patients aged from 14 to 58 years from three different Belgian families. All three familial pathogenic variants are frameshifts, localised in the last exon of PMEPA1 and predicted to lead to a truncated protein. All variants have already been reported in the literature in patients presenting with FTAAD.
Cardiovascular anomalies were present in six patients and included two aortic dissections, enlarged abdominal aorta, dilatation of the pulmonary artery and mitral valve prolapse. Congenital heart malformations, such as a bicuspid aortic valve or an atrial septal defect, were found in three patients. Thoracic scoliosis was described in three patients and in addition pes planus and pectus excavatum were found in two patients. The two youngest patients presented an umbilical hernia, of which the male also presented bilateral cryptorchidism. Myopia was reported in two patients. Craniofacial dysmorphisms included high palate and downslanting palpebral fissures as the most frequent features (n=3), only one patient presented a hypertelorism and none had a bifid uvula. Other features included allergy in one patient and an autoimmune hypothyroidism in two patients.
In conclusion, aortic and cardiovascular abnormalities are the most common features. Other non-vascular features are inconsistently associated. Thus, there is a highly individual and familial variable expressivity of the LDS associated with the PMEPA1 gene variants in reported Belgian families. A close follow-up of these patients would allow a better understanding of the natural evolution of this new subtype of LDS.