Marfan Syndrome Associated With Intellectual Disability and Behavioral Anomalies: Further Evidence for the Effect of Compound Heterozygous Variants in <scp> <i>FBN1</i> </scp> on Phenotypic Severity

Marfan syndrome (MFS) is a rare connective tissue disorder characterized by involvement of the cardiovascular, ocular, and musculoskeletal systems. Pathogenic variants in FBN1 cause most of the MFS cases; however, intellectual disability (ID) is rarely observed. A non-consanguineous Pakistani family with four affected individuals was recruited. Physical examinations, echocardiography, and doppler ultrasound were performed as part of the clinical assessment. Exome sequencing was conducted on the index patient, and Sanger sequencing was performed for the entire family. ID was the primary symptom in all the affected individuals. A detailed examination showed that all affected individuals and their affected mother were tall, had long limbs, craniofacial abnormalities, and exhibited low IQ, aggressive, and hyperactive behaviors. Heart defects, such as atrial septal defects and pulmonary hypertension, were observed in one affected individual and her mother. Genetic analysis identified two rare missense variants in FBN1, c.1552G>A (p.Gly518Arg) and c.3046A>G (p.Thr1016Ala), both predicted to be deleterious. The p.Gly518Arg variant is predicted to be likely pathogenic, while the p.Thr1016Ala variant is of uncertain significance. Notably, these variants were found in two affected individuals in a compound heterozygous state, correlating with more severe symptoms. Each variant alone, seen in the two patients, is associated with milder symptoms, indicating incomplete penetrance. In conclusion, this study identified rare heterozygous missense variants in FBN1, suggesting a potential connection between neurodevelopmental outcomes and variants in FBN1. However, further research is needed to clarify the role of FBN1 in ID.