Understanding the Genetics of Polydactyly in Humans Just Got Easier

Understanding the Genetics of Polydactyly in Humans
Polydactyly is a congenital genetic disorder that causes the affected individual to exhibit additional digits on the hands and/or feet. These digits may just be a mass of tissue or a fully functional digit. HealthHearty explores and discusses the true genetic basis for the emergence of this particular condition.
Did You Know?
Akshat Saxena, from India, holds the world record for the highest number of digits. He possesses 7 digits on each hand, and 10 digits on each foot, making it a total of 34 digits.
Polydactyly or polydactylism is a term derived from the Greek words 'polys', meaning 'many', and 'daktylos', meaning 'finger'. It is also called hyperdactyly, and involves the development of supernumerary fingers or toes in an individual. In other words, people affected by this condition exhibit more than 5 fingers/toes on each hand/foot. It has an incidence of 1 in every 500 live births, and is seen to be more common in people from African origins as compared to those of Caucasian descent. It is also more common in males than females.

The extra digit may present itself in three possible ways: a mass of tissue and muscle; tissue and a bony growth devoid of any joints; or tissue and bone with a joint, making it functional. The level of functionality increases with the increase in the level of bone development. This also increases the surgical difficulty in removing this outgrowth, if required. This condition can be diagnosed by carrying out physical examinations and X-rays of the additional digit. Ultrasound can be used to detect it during the course of pregnancy as well. The course of treatment is decided based on the degree of development of the digit.

The extra digit may appear in three locations along the hand or foot. It most commonly appears on the ulnar (little finger) side of the hand. Less common is its appearance on the radial (thumb) side of the hand, and it is extremely rare to be found within the middle three digits. These presentations are used as a basis to classify polydactyly into its various types: Ulnar or postaxial, radial or preaxial, and central polydactyly. The extra digit in these conditions is most often due to an abnormal forking in the existing digit during its development, or it may originate from the wrist itself, as in the case of a normal digit.
Genetic Basis of Polydactyly
Polydactyly can occur by itself, as a part of a congenital syndrome. Based on this, the inheritance pattern of this condition varies. If it is a single gene disorder, manifesting by itself, then it is most likely due to an error in the GLI3 zinc finger gene, and it shows an autosomal dominant inheritability. Hence, only one copy of the mutated gene is enough to induce this condition. Also, if at least one parent has this presentation, then each progeny has a 50% chance of inheriting the trait.

However, there have been multiple documented cases of polydactyly occurring in association with syndromic disorders. In such a case, the inheritance of the trait depends on the type of genetic errors, as well as the genes involved in that particular disorder. In other words, in case of a syndromic presentation, the condition may arise due to genetic mutation in genes other than GLI3. Also, the inheritance pattern will be determined by the genes associated with the particular syndrome. This multifactorial case may follow the patterns of autosomal recessive or X-linked trait. In case the trait is autosomal recessive, both parents must carry at least one copy of the mutated gene (carriers), for the child to develop this trait. If both or either one of the parents do not possess the mutated gene, then the child is born with a normal set of 5 digits on each hand and foot.

On the other hand, if the condition is sex-linked, there are two possibilities. The defunct gene may be X-linked or Y-linked. This discernment is important, as the X-linked inheritance pattern can be dominant or recessive. This is possible due to the fact that, both male and females possess at least one X chromosome. Here, if the trait is dominant, all progeny are affected, but if the trait is recessive, it will only be seen in case of females. On the other hand, in case of Y-linked inheritance, there is only dominant inheritance, hence, the males will show polydactyly, and so will their male offspring. It may sometimes be difficult to even decipher the mode of inheritance due to the interactions of the involved genes, and there have been cases of spontaneous cases of polydactyly.

This leads to the conclusion that, the condition follows a very varied pattern of inheritance, which is based on factors like family history, spontaneous mutations, nature of mutation, gene affected, etc. Hence, it is impossible to ascribe a universal genetic basis to the propagation of this condition in the population. The exact pattern can differ from individual to individual, based on his/her genetic makeup. The following table outlines a few syndromic and non-syndromic presentations of polydactyly, accompanied by the genes involved, and the mode of their inheritance.
Associated Disorder Genes Involved Inheritance
Achondrogenesis, Type II COL2A1 Autosomal Recessive
Acrocallosal Syndrome GLI3 Autosomal Recessive
Apert Syndrome FGFR2 Autosomal Dominant
Asphyxiating Thoracic Dystrophy IFT80, DYNC2H1 Autosomal Recessive
Atelosteogenesis Type III FLNB Autosomal Dominant
Baller-Gerold Syndrome RECQL4 Autosomal Recessive
Bardet-Biedl Syndrome BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, BBS11, BBS12 Autosomal Recessive
Basal Cell Nevus Syndrome PTCH1 Autosomal Dominant
Beckwith-Wiedemann Syndrome CDKN1C Autosomal Dominant
Bloom Syndrome RECQL3 Autosomal Recessive
Brachydactyly Type B ROR2 Autosomal Dominant
Brachydactyly Type C GDF5 Autosomal Dominant
Branchiooculofacial Syndrome TFAP2A Autosomal Dominant
C Syndrome CD96 Autosomal Dominant
C-LIKE Syndrome CD96 Autosomal Dominant
Carpenter Syndrome RAB23 Autosomal Recessive
CHAR Syndrome TFAP2B Autosomal Dominant
CHARGE Syndrome CHD7, SEMA3E Autosomal Dominant
Chondrodysplasia, Grebe Type GDF5 Autosomal Recessive
Chondrodysplasia Punctata 2 EBP Sex-linked
Craniofrontonasal Syndrome EFNB1 Sex-linked
De Smet Complex Synpolydactyly FBLN1 Autosomal Dominant
Chondrodystrophy; Advanced Bone Age CANT1 Autosomal Recessive
Diamond-Blackfan RPS19, RPL5, RPL11 Autosomal Recessive
Duane-Radial Ray Syndrome SALL4 Autosomal Dominant
Ectrodactyly WNT10A Multiple modes
Ellis-Van Creveld Syndrome EVC, EVC2 Autosomal Recessive
Endocrine-cerebro-steodysplasia ICK Autosomal Recessive
Fanconi Pancytopenia Syndrome FANCA, FANCB, BANCC, FANCD1, FANCD2, FANCE, FANCF, XRCC9, FANCI, FANCJ, PHF9, FANCM, FANCN, FANCO Autosomal Recessive
Fibular Aplasia or Hypoplasia WNT7A Autosomal Recessive
Focal Dermal Hypoplasia PORCN Sex-linked
Frontonasal Dysplasia ALX3 Multiple modes
Greig Cephalopolysyndactyly Syndrome GLI3 Autosomal Dominant
Holoprosencephaly GLI2 Autosomal Dominant
Holt-Oram Syndrome TBX5 Autosomal Dominant
Hydrolethalus Syndrome 1 HYLS1 Autosomal Recessive
Hydrops-Ectopic Skeletal Dysplasia LBR Autosomal Recessive
Joubert Syndrome CXORF5, INPP5E, TMEM216, RPGRIP1L Multiple modes
Lacrimoauriculodentodigital Syndrome FGFR2, FGFR3, FGF10 Autosomal Dominant
Lathosterolosis SC5DL Autosomal Recessive
McKusick-Kaufman Syndrome MKKS Autosomal Recessive
Meckel Syndrome CC2D2A, CEP290, MKS1, TMEM67, RPGRIP1L Autosomal Recessive
Nijmegen Immunodeficiency Syndrome NBN Autosomal Recessive
Oculo-dento-digital Syndrome GJA1 Autosomal Dominant
Otopalatodigital Syndrome, Type II FLNA Sex-linked
Pallister-Hall Syndrome GLI3 Autosomal Dominant
Polydactyly, Postaxial GLI3 Multiple modes
Polydactyly, Preaxial SHH, ZRS Autosomal Dominant
Renal-Hepatic-Pancreatic Dysplasia NPHP3 Autosomal Recessive
Robinow-Sorauf Syndrome TWIST Autosomal Dominant
Rubinstein-Taybi Syndrome CBP Autosomal Dominant
Schinzel-Giedion Midface-Retraction Syndrome SETBP1 Autosomal Recessive
Simpson-Golabi-Behmel Syndrome, Type I GPC3 Sex-linked
Smith-Lemli-Opitz Syndrome DHCR7 Autosomal Recessive
Syndactyly SHH,
Autosomal Dominant
Synpolydactyly HOXD13 Autosomal Dominant
Thanatophoric Dysplasia, Type I FGFR3 Autosomal Dominant
Tibial Hemimelia-Polydactyly-Club Foot PITX1 Autosomal Dominant
Townes-Brocks Syndrome SALL1 Autosomal Dominant
Ulnar-Mammary Syndrome TBX3 Autosomal Dominant
Weyers Acrofacial Dysostosis EVC Autosomal Dominant
It must be noted, however, that the condition arises not only as a result of mutations in the genes themselves, but also due to errors in cis-regulatory elements responsible for the expression of a specific gene, or errors in signal transduction pathway molecules. Also, there are documented cases of sporadic occurrences of polydactyly caused due to disruption of cells during embryonic development. Such spontaneous cases are not heritable.
This condition occurs not only in humans, but also is cats and dogs. It is also a common trait in chicken and mice. Evolutionary research suggests that, such mutations cause a revertion to ancestral phenotypes, since approximately 375 million years ago, there existed tetrapods possessing as many as 8 digits per appendage. This suggests that somewhere along the evolutionary timeline, the extra fingers were shed off, and the five-finger plan emerged as the predominant form. This notion is supported by the fact that, various animals that have evolved in parallel to humans also possess the five-finger skeletal structure. These include dolphins, bats, cats, dogs, mice, etc.