Synpolydactyly (SPD) is a joint presentation of syndactyly (fusion of digits) and polydactyly (production of supernumerary digits) [1] [2] . SPD affects both hands and feet, often occurring symmetrically on both body sides [3] . This is often a result of a mutation in the HOXD13 gene [2] , as HOXD genes are necessary in early limb bud development and specification of the limbs [4] .
SPD is inherited in an autosomal dominant pattern, meaning that an individual only needs to inherit one copy of the affected gene, also known as an allele, from either parent to potentially develop the condition. However, not everyone who inherits the affected allele will show symptoms (incomplete penetrance) [1] ., and the symptoms can vary greatly in type and severity among those who are affected (variable expressivity) [1] .
The most studied variant, SPD1, is commonly caused by an increase in polyalanine repeats at the start of the HOXD13 gene [4] . This likely disrupts proper protein function, as polyalanine consists of alanine amino acids, which make up proteins [4] . The number of repeats have been found to be related to the degree to which the individual is affected [5] . For 6 polyalanine residues or less, the effects are mild. However, a larger number of polyalanine repeats in the gene causes more severe effects.
Over the past years genetic changes causing the HOXD13 gene to be shorter than normal have also been found among individuals [4] . More recently, research has found a single change in the code for the HOXD13 gene present in a family with synpolydactyly [6] . The study suggests that this genetic change causes an increase in osteoclasts, which are cells that break down bone [6] .This is still an emerging area of research.
Synpolydactyly type 1 (SPD1), also known as syndactyly type II, is a genetic limb disorder caused by inheritance of at least one rare allele of the HOXD13 gene [7] .
In heterozygous cases, where individuals have one rare HOXD13 allele, common symptoms include fused third and fourth fingers, sometimes with an extra small finger within the webbing [8] [9] . The feet may show skin webbing between the fourth and fifth toes. However, not all carriers display symptoms, a phenomenon known as incomplete penetrance [10] .
In homozygous cases, where individuals have two rare HOXD13 alleles, they experience finger fusions, as well as more severe symptoms such as significantly shortened hand and toe bones [11] , and the big toe can be noticeably long and angled inward [9] . Additionally, the metacarpal bones (hand) may take on the shape of carpal bones (wrist) [9] [10] . These traits often include finger fusions but can vary widely [10] and overlap with symptoms of synpolydactyly, thus no single feature defines SPD1.
SPD1 symptoms vary widely among individuals and can be grouped into varying levels of severity [2] : mild features, such as inward curvature of the pinky finger in some heterozygous cases [2] , common SPD1 traits like fusion of the third and fourth fingers and extra digits that appear in both heterozygous and some homozygous individuals [12] , and severe symptoms like multiple fused fingers and shortened bones [9] found only in homozygous cases. This range of symptoms suggests variable expressivity, indicating that additional genetic or environmental factors may play a role in influencing how the HOXD13 gene is expressed [8] .
Treatment options for synpolydactyly aim to improve both the functionality and aesthetics of the affected hands and feet. Mild cases may be managed by removing extra digits. Moderate cases often require surgical separation of fused digits and widening of the interdigital space to enhance mobility and appearance. Severe cases may need complex reconstructive procedures, such as repositioning bones and separating them, and skin grafting might also be necessary in some instances [13] .
Post-surgical outcomes typically include reduced pain, improved mobility, and greater independence in daily activities [3] .
An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and the second is called recessive. This state of having two different variants of the same gene on each chromosome is originally caused by a mutation in one of the genes, either new or inherited. The terms autosomal dominant or autosomal recessive are used to describe gene variants on non-sex chromosomes (autosomes) and their associated traits, while those on sex chromosomes (allosomes) are termed X-linked dominant, X-linked recessive or Y-linked; these have an inheritance and presentation pattern that depends on the sex of both the parent and the child. Since there is only one copy of the Y chromosome, Y-linked traits cannot be dominant or recessive. Additionally, there are other forms of dominance, such as incomplete dominance, in which a gene variant has a partial effect compared to when it is present on both chromosomes, and co-dominance, in which different variants on each chromosome both show their associated traits.
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 5% will not.
Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.
A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of loci. The specific case of heterozygote advantage due to a single locus is known as overdominance. Overdominance is a rare condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents, and heterozygous individuals have a higher fitness than homozygous individuals.
In genetics, expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype. Alternatively, it may refer to the expression of a particular gene by individuals having a certain phenotype. Expressivity is related to the intensity of a given phenotype; it differs from penetrance, which refers to the proportion of individuals with a particular genotype that share the same phenotype.
Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product. Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.
Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate (CL/P), and cleft palate only (CPO). The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve CL/P. VWS is distinct from other clefting syndromes due to the combination of cleft lip and palate (CLP) and CPO within the same family. Other features frequently associated with VWS include hypodontia in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities, syndactyly of the hands, polythelia, ankyloglossia, and adhesions between the upper and lower gum pads.
Metachondromatosis is an autosomal dominant, incompletely penetrant genetic disease affecting the growth of bones, leading to exostoses primarily in the hands and feet as well as enchondromas of long bone metaphyses and iliac crests. This syndrome affects mainly tubular bones, though it can also involve the vertebrae, small joints, and flat bones. The disease is thought to affect exon 4 of the PTPN11 gene. Metachondromatosis is believed to be caused by an 11 base pair deletion resulting in a frameshift and nonsense mutation. The disease was discovered and named in 1971 by Pierre Maroteaux, a French physician, when he observed two families with skeletal radiologic features with exostoses and Ollier disease. The observation of one family with five affected people led to the identification of the disease as autosomal dominant. There have been less than 40 cases of the disease reported to date.
In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other. Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.
Muenke syndrome, also known as FGFR3-related craniosynostosis, is a human specific condition characterized by the premature closure of certain bones of the skull during development, which affects the shape of the head and face. First described by Maximilian Muenke, the syndrome occurs in about 1 in 30,000 newborns. This condition accounts for an estimated 8 percent of all cases of craniosynostosis.
Lethal alleles are alleles that cause the death of the organism that carries them. They are usually a result of mutations in genes that are essential for growth or development. Lethal alleles can be recessive, dominant, conditional, perinatal, or postnatal after an extended period of apparently normal development depending on the gene or genes involved.
Pseudodominance is the situation in which the inheritance of a recessive trait mimics a dominant pattern.
Homeobox protein Hox-D13 is a protein that in humans is encoded by the HOXD13 gene. This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms.
An obligate carrier is an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner.
Zygosity is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Liebenberg syndrome is a rare autosomal genetic disease that involves a deletion mutation upstream of the PITX1 gene, which is one that's responsible for the body's organization, specifically in forming lower limbs. In animal studies, when this deletion was introduced to developing birds, their wing buds were noted to take on limb-like structures.
Familial opposable triphalangeal thumb duplication is a limb malformation syndrome and a type of pre-axial polydactyly, characterized by having duplicated opposable triphalangeal thumbs. This condition can be a symptom of other genetic disorders, such as Holt–Oram syndrome and Fanconi anemia. This trait is autosomal dominant and often runs in families. Sometimes big toe duplication, post-axial polydactyly, and syndactyly of the hand and feet can occur alongside this malformation Approximately 20 families with the condition have been described in medical literature.
Du Pan syndrome, also known as fibular aplasia-complex brachydactyly syndrome, is an extremely rare genetic condition. Unlike other rare genetic conditions, Du Pan syndrome does not affect brain function or the appearance of the head and trunk. This condition is associated with alterations to the GDF5 gene. The way that this condition is passed on from generation to generation varies, but it is most commonly inherited in an autosomal recessive manner, meaning two copies of the same version of the gene are required to show this condition. Rare cases exist where the mode of inheritance is autosomal dominant, which means having only one version of the gene is enough to cause this condition.
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