SMAD3 and Fryns syndrome: Particularly, the suspected causal relationships between variants in PIGW for a Fryns syndrome phenotype, KIF4A as a player in the L1CAM pathway for X-linked hydrocephalus and variants in SMAD3 which may cause agnathia-otocephaly as the severe end of the Loeys-Dietz spectrum emphasize the importance of clinical and developmental genetics review in addition to formal variant assessment.