Understanding the genetic basis of Acrofrontofacionasal Dysostosis 1

Our project deals with a rare human syndrome called Acrofrontofacionasal Dysostosis 1 (AFFND1). In general, the dysostoses are diseases due to defects in embryonic development; different skeletal compartment can be affected (cranium, face, axial or appendicular skeleton) and symptoms at other organs can also be present. In particular, AFFND1 is characterized by short stature, mental retardation, facial dysmorphisms such as abnormally increased distance between the eyes and cleft lip/palate; finger abnormalities such as bending of the middle joint of a finger, shortening of the fingers and toes due to unusually short bones, presence of extra digits or fusion of digits, and hypoplastic fibula. So far, the disease has been reported only in 3 Brazilian families and in one of Indian origin. An autosomal recessive pattern of inheritance has been hypothesized, but the specific genetic defect is unknown. Here we aim to unravel the molecular basis of the disease. To this end, we have collected DNA from the families described and will perform exome sequencing, which is the sequencing of the fraction of the genome enriched in protein-coding regions and will lead to a list of variants spread throughout the genome. We will exclude variants commonly found in the healthy population; the remaining ones will be prioritized using bioinformatics tools able to predict whether a change might be deleterious or tolerated. For selected variants we will verify the transmission together with the disease within affected families, sequence the entire gene in other patients with a similar phenotype and perform expression studies. Overall, our research will allow establishing a precise molecular diagnosis in these patients and offering the possibility of genetic counseling to their families. Moreover, our results might highlight new mechanisms relevant to early developmental stages and possibly involved also in similar pathologies.