There are multiple genetic causes (genetic heterogeneity) of split hand/foot malformation which makes it difficult to pinpoint a single causative mutation that leads to the condition.
Split hand/foot malformation can be inherited in an autosomal dominant pattern in some families, autosomal recessive in some families, and X-linked in others. SHFM also occurs as a result of a random (sporadic) mutation during fertilization or embryonic development. When one limb is affected, the cause is often a new gene mutation. However, when four limbs are affected, the cause is often an inherited gene mutation.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. Twelve different types of SHFM have been mapped to different human chromosomes with new gene locations (loci) continually being identified by researchers. The first eight types of SHFM include the type 1 isolated split hand/foot malformation symptoms whereas other subtypes are type 2 with long-bone deficiencies. SHFM1 has been mapped to chromosome 7q21, SHFM2 to Xq32, SHFM3 located to 10q24, SHFM4 to 3q27, SHFM5 to 2q31, SHFM6 to 12q13.11q13, and other loci in the 8q21.11q22.3 region. There are additional types of SHFM with long bone deficiency that map to chromosomes 1q42.2q43, 6q14.1 and 17p13.3.
There are other subtypes of SHFM with long bone deficiency (SHFLD) that typically follow autosomal dominant inheritance and have specific genetic causes. Individuals with SHFLD often have deformities in their tibia and fibula and this has been associated with three loci. SHFLD1 has been mapped to a region spanning 1q42.4q43, SHFLD2 to 6q14.1, and SHFLD3 to a region in 17p13.1p13.3. Researchers have narrowed down the association of SHFLD3 to the BHLHA9 gene in a single family, but more validation is required.
SHFM1 has also been associated with mutations in the DLX5 and DLX6 genes, both members of the WNt signaling pathway, which is known to be important for limb development in embryogenesis. The role of these genes in causing ectrodactyly (the absence of fingers and/or toes) has been shown in knockout mice with no DLX5 and DLX6 genes. These mice presented with significant forms of ectrodactyly.
SHFM2 shows a unique X-linked inheritance of ectrodactyly that has only been recorded in one family related by blood (consanguineous). Further linkage analysis mapped this association to Xp26, and possible gene candidates are FGF13 and TONDU.
SHFM3 ectrodactyly maps to the 10q24 region of chromosome 10, and the responsible genetic mutation found here is a tandem duplication. This duplication actually accounts for 20% of SHFM cases. There are several genes affected by the duplication: DACTYLIN (SFHM3), BTRC, POLL, FGF8, and LBX1.
SHFM4 is caused by a loss of function mutation in the TP63 gene. TP63 has been shown to be important in tissue layering (epithelial stratification). It is uniquely inherited in an autosomal dominant fashion. Mice lacking p63 protein have been shown to have significant defects in proper limb development and/or limb shortening.
SHFM5 is seen in individuals who have deletions of the entire HOXD cluster. HOX genes are important for limb development and proper growth. Deletions of HOX genes can be causative for many growth aberrations including ectrodactyly and monodactyly.
SHFM6 is another subtype of ectrodactyly and is caused by mutations in the 12q13 locus. It is uniquely caused by autosomal recessive mutations in the DLX5 and Wnt genes, and has been only seen in three reported families. Mutations in Wnt genes have been shown to be necessary, but not sufficient in producing SHMF.
SHFM7 with mesoaxial polydactyly, the addition of another finger or toe, (SHFMMP) has been shown to be caused by mutations in the ZAK gene. Mesoaxial polydactyly is the presence of more than 5 digits not including the thumb or toe with the associated fusing of some bones. Homozygous missense mutations and homozygous intragenic deletions have also been shown in affected patients
SHFM8 is another form of ectrodactyly with mild-to-severe symptoms that is caused by mutations in the EPS15L1 gene. Some of the mutations reported include frameshift deletions, nonsense mutations, and other variants that lead to decreased amounts of EPS15L1 protein. The EPS15L1 protein has a unique role in embryonic development and neurogenesis.