Polydactyly and syndactyly are due to errors in the process of fetal development. For example, syndactyly results from the failure of the programmed cell death that normally occurs between digits. Most often these errors are due to genetic defects.

Polydactyly and syndactyly can both occur by themselves as isolated conditions or in conjunction with other symptoms as one aspect of a multi-symptom disease. There are several forms of isolated syndactyly and several forms of isolated polydactyly; each of these, where the genetics is understood, is caused by an autosomal dominant gene. This means that since the gene is autosomal (not sex-linked), males and females are equally likely to inherit the trait. This also means that since the gene is dominant, children who have only one parent with the trait have a 50% chance of inheriting it. However, people in the same family carrying the same gene can have different degrees of polydactyly or syndactyly.

Polydactyly and syndactyly are also possible outcomes of a large number of rare inherited and developmental disorders. One or both of them can be present in over 100 different disorders where they are minor features compared to other characteristics of these diseases.

For example, polydactyly is a characteristic of Meckel syndrome and Laurence-Moon-Biedl syndrome. Polydactyly may also be present in Patau's syndrome, asphyxiating thoracic dystrophy, hereditary spherocytic hemolytic anemia, Moebius syndrome, VACTERL association, and Klippel-Trenaunay syndrome.

Syndactyly is a characteristic of Apert syndrome, Poland syndrome, Jarcho-Levin syndrome, oral-facial-digital syndrome, Pfeiffer syndrome, and Edwards syndrome. Syndactyly may also occur with Gordon syndrome, Fraser syndrome, Greig cephalopolysyndactyly, phenylketonuria, Saethre-Chotzen syndrome, Russell-Silver syndrome, and triploidy.

In some isolated cases of polydactyly or syndactyly, it is not possible to determine the cause. Some of these cases might nevertheless be due to genetic defects; sometimes there is too little information to demonstrate a genetic cause. Some cases might be due to external factors like exposure to toxins or womb anomalies.