Abstract
Limb development is clinically and biologically important. Polydactyly is common and caused by aberrant anterior-posterior patterning. Human disorders that include polydactyly are diverse. To facilitate an understanding of the biology of limb development, cataloging the genes that are mutated in patients with polydactyly would be useful. In 2002, I characterized human phenotypes that included polydactyly. Subsequently, many advances have occurred with refinement of clinical entities and identification of numerous genes. Here, I update human polydactyly entities by phenotype and mutated gene. This survey demonstrates phenotypes with overlapping manifestations, genetic heterogeneity, and distinct phenotypes generated from mutations in single genes. Among 310 clinical entities, 80 are associated with mutations in 99 genes. These results show that knowledge of limb patterning genetics is improving rapidly. Soon, we will have a comprehensive toolkit of genes important for limb development, which will lead to regenerative therapies for limb anomalies.
Keywords: malformations, genetic heterogeneity, medical diagnosis, pleiotropism
INTRODUCTION
Polydactyly results from defective patterning of the anterior-posterior axis of the developing limb and can occur as a simple or isolated malformation or as part of a pleiotropic developmental anomaly syndrome. Polydactyly is an important manifestation in clinical medicine not only because it has cosmetic and functional implications and often necessitates surgical treatment, but because it can serve as an immediately recognizable indicator that the patient, particularly a newborn, has a multiple congenital anomaly syndrome (pleiotropic developmental anomaly syndrome). For these reasons, it is important for the clinician to be prepared to evaluate the patient for polydactyly and consider the myriad syndromes that may be associated with this anomaly. In addition to the clinical manifestations, polydactyly can be considered by the scientist as an experiment of nature, in that the manifestation of this phenotype points to an underlying mutated gene or teratogen that is associated with a perturbation of the molecular machinery of limb development [Towers and Tickle 2009]. The elucidation of the etiologies of polydactyly can serve as a tool to facilitate the dissection of the genetic and signaling pathways that underlie polydactyly, specifically, that of anterior-posterior specification of the limb (for recent review, see [Butterfield et al., 2010]).
For both clinical utility and to facilitate basic science investigations, it is useful to catalog the phenotypes that include polydactyly as a manifestation. In 2002, I cataloged the entities recognized by geneticists in the clinic that included polydactyly as a manifestation [Biesecker 2002]. At that time, 97 clinical entities were listed, of which 37 were associated with mutations in one or more genes. Since that time, much progress has been made in molecular genetics of disease and it seemed appropriate to update this review*. In this article I will delineate the disorders that have been associated with polydactyly, delineate the genes that are altered in these disorders, and speculate on the future implications of these data.
Methods
To tabulate syndromic and isolated polydactyly clinical entities, I drew from several sources. First, Mendelian Inheritance in Man [Anon. 2010] was searched using the term “*polydactyl*”. Second, the Winter-Baraitser Medical Database (WBDD, Ref) was interrogated using the following terms: “postaxial polydactyly of fingers”, “postaxial polydactyly of toes”, “preaxial polydactyly of fingers”, “preaxial polydactyly of toes”, “meso-axial polydactyly of fingers”, “mesoaxial polydactyly of toes”, “palmar polydactyly”, “polydactyly/bifid thumb”, “polydactyly bifid hallux”, “mirror image polydactyly of fingers”, and “mirror image polydactyly of toes”. Third, the tabular listings of polydactyly in the appendix of Smith’s Recognizable Patterns of Malformation [Jones and Smith 2006] and Tables 21-1 – 21-7 of the chapter “Hands and Feet” in Human Malformations and Related Anomalies [Stevenson 2006], were reviewed. These lists were merged and duplicate entries were deleted, although, as will be noted in the discussion, this can be challenging. In contrast to the prior analysis, I included entities where only a single family or case was described. Some of these disorders must be considered as candidate polydactyly syndromes as it is possible in some cases that the association of polydactyly in these traits was coincidental. Many of these ultra rare or unique cases emanated from the Winter-Baraitser Dysmorphology Database. If a common malformation syndrome had a single case with polydactyly, that entity was deleted from this analysis, as it seemed more likely that it was coincidental, rather than causal. For rare malformation syndromes, it can be difficult to determine if a particular manifestation is uncommon or coincidental. In these cases, the entity was generally included in the listing. It can also be challenging to determine the boundaries of the descriptor of polydactyly itself. For example, broad thumbs or great toes are potentially mechanistically related to anterior-posterior patterning. There is a large degree of inter-individual variation in the width of these digits, arguing against inclusion of this finding as part of the spectrum of polydactyly. In contrast, in disorders with preaxial polydactyly (e.g., Greig cephalopolysyndactyly syndrome) a full spectrum of abnormalities are observed, including complete digit duplication, partial duplication, U shaped or forked distal phalanges, and broad digits, arguing for inclusion. In this review, I generally required frank polydactyly to be reported in the entity for it to be included. Next, entries that described polydactyly only in model organisms and entities that were associated with segmental aneusomy (and not with a specific gene) or teratogens were deleted. This is not because these entities are unimportant for understanding limb development. Instead, this was done because the purpose of this review was to review the genes that contribute to polydactyly and it can be difficult to identify the gene products that are pathogenetically important in many teratogens and segmental aneusomy syndromes. Entries that separately described a gene and a disorder (e.g., GLI3 and Pallister-Hall syndrome) were reduced to a single clinical entry. In recent years, there has been evolution of the MIM database with regard to clinical and gene entries. For some disorders, MIM has consolidated the clinical data into a single entry (e.g., Bardet-Biedl syndrome MIM 209900) with additional entries for the genes, and the gene entries have little or no clinical data. For other phenotypes, such as asphyxiating thoracic dystrophy (Jeune) and Meckel syndromes, there are multiple entries with genetic and clinical data. The general approach in this review was to treat clinically distinct phenotypes as single entities, independent of genotype [Robin and Biesecker 2001]. As is well known to clinical geneticists, it can be difficult to determine the boundaries that distinguish some clinical entities from overlapping disorders. For example, it can be challenging to clinically distinguish a mildly affected case of Jeune syndrome (MIM 208500) from Ellis-Van Creveld syndrome (MIM 225500). In addition, current standards of clinical data reporting and limitations of commonly used terminology limit the ability to finely parse the data in the clinical literature [Allanson et al., 2009; Biesecker 2005]. For this reason, it can be difficult to accurately determine the presence or absence of some malformations in clinical reports, much less to know the precise form of that manifestation – for example, whether a case of polydactyly was postaxial or central. As well, it can be difficult to distinguish entities that have both syndromic and non-syndromic manifestations, such as Greig Cephalopolysyndactyly syndrome (MIM 175700) and Crossed Polydactyly (MIM 174700), both of which can be caused by mutations in GLI3 [Biesecker 2006]. In these cases, I generally deferred to the curators of MIM, WBDD, and the Stevenson et al textbook regarding the delineation of these entities. With respect to genes, this is generally straightforward to tabulate, with the exception of regulatory elements. Three entries were associated with such elements of the SHH and SOX9 genes.
Results and Discussion
This resulting list comprised 310 entries of disorders that include polydactyly, including syndromic (290 entries) and nonsyndromic (20 entries) forms (Table I). This list is significantly larger than that from the 2002 review, primarily owing to the addition of the WBDD entities, improved curation, as well as general advances in medical knowledge. These 310 entities show a full range of Mendelian inheritance patterns, including autosomal dominant (73), autosomal recessive (103), X-linked (12), more than one inheritance pattern (9), but many had an unknown mode of inheritance (113).
Table I.
Clinical Entities That Manifest Polydactyly
| Source | Inheritance | Clinical Entity | Gene |
|---|---|---|---|
| 147800 | D | Aase Smith Syndrome Type I | |
| 200610 | R | Achondrogenesis, Type II | COL2A1 |
| 201050 | R | Acro-Cranio-Facial Dysostosis | |
| 200990 | R | Acrocallosal Syndrome | GLI3 |
| 200995 | R | Acrocephalopolysyndactylous Dysplasia | |
| 201020 | R | Acrocephalosyndactyly Type I | |
| * | U | Acrofacial Dysostosis | |
| 201170 | R | Acrofacial Dysostosis-Type Rodriguez | |
| 201180 | R | Acrofrontofacionasal Dysostosis Type 1 | |
| 239710 | R | Acrofrontofacionasal Dysostosis Type 2 | |
| 603671 | D | Acromelic Frontonasal Dysostosis | |
| 605967 | D | Acropectoral Syndrome | |
| 102510 | D | Acropectorovertebral Dysplasia, F-form of | |
| 102520 | U | Acrorenal | |
| 200980 | R | Acrorenal-Mandibular Syndrome | |
| * | U | Adamsbaum (1991) Syndrome | |
| 600325 | U | Aminopterin Syndrome sine Aminopterin | |
| * | U | Anandan (2008) Sternal Defects – Aplasia Cutis Congenita-Polydactyly | |
| 101200 | D | Apert Syndrome | FGFR2 |
| * | U | Arens (1991) Acrofacial Dysostosis | |
| 243910 | R | Arimia Syndrome | |
| 208500 611263 613091 |
R | Asphyxiating Thoracic Dystrophy | IFT80, DYNC2H1 |
| 108721 | D | Atelosteogenesis Type III | FLNB |
| * | U | Baisch-Polydactyly; Absent Nails | |
| 218600 | R | Baller-Gerold Syndrome | RECQL4 |
| * | U | Baraitser-Brachyphalangy-Polydactyly-Absent Tibiae | |
| * | U | Barakat (1996) Polydactyly-Osteopenia-Hypoplastic Kidney | |
| 209900 | R | Bardet-Biedl Syndrome | BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, BBS11, BBS12 |
| 109400 | D | Basal Cell Nevus Syndrome | PTCH1 |
| * | U | Bates (2002) Acrofacial Dysostosis-Digital Anomalies-Renal Agenesis | |
| 130650 | D | Beckwith-Wiedemann Syndrome | CDKN1C |
| 210350 | R | Biemond Syndrome II | |
| * | U | Bitoun (1994)-Glaucoma-Thumb Anomalies-Joint Dislocations | |
| * | R | Blair (2000) Autosomal Recessive Craniosynostosis Syndrome | |
| 210900 | R | Bloom Syndrome | RECQL3 |
| 263630 | R | Bonneau Syndrome | |
| 112450 | D | Brachydactyly (Preaxial) Hallux Varus-Thumb Abduction | |
| 113000 | D | Brachydactyly Type B | ROR2 |
| 113100 | D | Brachydactyly Type C | GDF5 |
| 609945 | D | Brachyphalangy, Polydactyly, and Tibial Aplasia/Hypoplasia | |
| * | U | Braddock (2003) Laryngeal Webs; CHD; Vertebral Defects | |
| 113620 | D | Branchiooculofacial Syndrome | TFAP2A |
| 256200 | R | Braun (1962) Nephrosis; Deafness; Brachytelephalangy | |
| 300404 | X | BRESHECK | |
| * | U | Brunoni (1984) Radial Aplasia; Short Stature; Unusual Face | |
| 211750 | D | C Syndrome | CD96 |
| 605039 | D | C-LIKE Syndrome | CD96 |
| 114150 | R | Camptobrachydactyly | |
| 201000 | R | Carpenter Syndrome | RAB23 |
| * | U | Carpenter-Hunter-Micromelia; Polysyndactyly; Encephalocele; Fragile Bones | |
| * | U | Cerebro-fronto-facial Syndrome Type III | |
| 213980 | R | Cerebrofaciothoracic Dysplasia | |
| 605627 | D | Cerebrooculonasal Syndrome | |
| 169100 | D | CHAR Syndrome | TFAP2B |
| 214800 | D | CHARGE Syndrome | CHD7, SEMA3E |
| * | U | Chitayat (1993) Hyperphalangism; Hallux Valgus; Bronchomalacia | |
| * | R | Chitty (1993) Bowed Tibiae; Radial Anomalies; Osteopenia; Fractures | |
| * | U | Chondrodysplasia-Situs Inversus-Cystic Pancreatic Dysplasia | |
| 200700 | R | Chondrodysplasia, Grebe Type | GDF5 |
| 302960 | X | Chonrdodysplasia Punctata 2, X-Linked Dominant | EBP |
| 601165 | R | Cleft Lip/Palate with Characteristic Facies, Intestinal Malrotation, and Lethal Congenital Heart Disease | |
| * | U | COH Syndrome-Craniosynostosis; Bifid Thumb; Micropenis | |
| 120400 | D | Colobomas-Brachydactyly (Type Sorsby) | |
| 601707 | U | Craniofacial Malformations, Asymmetric, with Polysyndactyly and Abnormal Skin and Gut Development | |
| 304110 | X | Craniofrontonasal Syndrome | EFNB1 |
| * | D | Culler (1984) Hypopituitarism; Postaxial Polydactyly | |
| * | U | Cutis Aplasia-Blue Sclerae-Hypertelorism-Polydactyly-Hypoplastic Nipples | |
| 219250 | U | Cutis Marmorata Telangiectasia Congenita | |
| 220220 | R | Dandy-Walker Malformation with Postaxial Polydactyly | |
| * | D | De Smet Complex Synpolydactyly | FBLN1 |
| 124480 | D | Deafness, Congenital and Onychodystrophy, Autosomal Dominant | |
| ** | U | Deafness, Onychodystrophy, Triphalangeal Thumbs | |
| 251450 | R | Desbuquois (1966)-Chondrodystrophy; Advanced Bone Age | CANT1 |
| 105650 | R | Diamond-Blackfan | RPS19, RPL5, RPL11 |
| 223200 | U | Disorganization, Mouse, Homolog of | |
| * | U | Donnai (1988) Meckel-like Syndrome | |
| 220500 | R | DOOR | |
| 126500 | U | Double Nail For Fifth Toe | |
| 607323 | D | Duane-Radial Ray Syndrome | SALL4 |
| * | U | Duplication of Lower Limb-Plus | |
| 129540 | U | Ectodermal Dysplasia Syndrome with Distinctive Facial Appearance and Preaxial Polydactyly of Feet | |
| 183600 | M | Ectrodactyly-Autosomal Dominant | WNT10A |
| 225290 | R | Ectrodactyly-Polydactyly | |
| 600002 | R | Eiken (1984) Retarded Ossification; Abnormal Modeling of Bones | PTHR1 |
| 225500 | R | Ellis-Van Creveld Syndrome | EVC, EVC2 |
| * | R | Encephalocele-Radial, Cardiac, Gastrointestinal, Anal/renal Anomalies | |
| 612651 | R | Endocrine-Cerebrosteodysplasia | ICK |
| * | R | Engelhard (1979) Pre- and Postaxial Polysyndactyly; Ptosis | |
| 612731 | R | Faciocardiomelic Syndrome | |
| 227650 | R | Fanconi Pancytopenia Syndrome | FANCA, FANCB, BANCC, FANCD1, FANCD2, FANCE, FANCF, XRCC9, FANCI, FANCJ, PHF9, FANCM, FANCN, FANCO |
| 228930 | R | Fibular Aplasia or Hypoplasia, Femoral Bowing and Poly-, Syn-, and Oligodactyly | WNT7A |
| 134780 | U | Femoral-Facial Syndrome | |
| * | U | Ferda Percin-Yilmaz-Syn-Poly-Oligo-Brachydactyly | |
| * | U | Fibular Aplasia-Anonychia-Finger Polydactyly-Toe Oligodactyly | |
| * | U | Fibular Hemimelia-Polysyndactyly | |
| 136140 | D | Floating-Harbor-Short Stature-Delayed Bone Age-Broad Nose | |
| * | U | Focal Dermal Hypoplasia, Morning Glory Anomaly, and Polymicrogyria | |
| 305600 | X | Focal Dermal Hypoplasia | PORCN |
| * | U | Franceschini (1994) Mask-Like Face; Ear Anomalies; Digital Malformations | |
| 609640 | D | Frias Syndrome | |
| 136760 | M | Frontonasal Dysplasia | ALX3 |
| 606155 | U | Fryns-Aftimos | |
| * | U | Fryns-Lagae-Rizzo-Polydactyly-Growth Retardation-Spasticity-Urogenital | |
| * | U | Gandhi (2008) | |
| * | U | Garrett-Tripp-MR; Polydactyly; Hair Absence; Dermatitis; Perthe’s Disease | |
| * | U | Giant Diencephalic Hamartoma-Facial Cleft-Ear and Eye Anomalies | |
| 138790 | U | Goiter, Multinodular, Cystic Renal Disease, and Digital Anomalies | |
| * | R | Goossens (2006) Congenital Heart Disease-Polydactyly-Ectopic Neuropituitary | |
| 175700 | D | Greig Cephalopolysyndactyly Syndrome | GLI3 |
| 610536 | U | Growth and Mental Retardation, Mandibulofacial Dysostosis, Microcephaly, and Cleft Palate | |
| * | U | Gül (2000)-Craniofacial Anomalies | |
| * | R | Guschmann (2001) Mesomelic Campomelia-Polydactyly-Dandy-Walker | |
| 234280 | R | Hallux Varus and Preaxial Polysyndactyly | |
| * | U | Hameed (1999) Acrocraniofacial Syndrome | |
| * | U | Happle-Tinschert Syndrome | |
| * | U | Hartsfield (1984) Holoprosencephaly; Ectrodactyly; Cleft Face | |
| 249670 | R | Heart-hand-Type 4-with Mesoaxial Hexadactyly | |
| 141400 | U | Hemifacial Microsomia-Radial Defects | |
| * | U | Hemihypertrophy-Hemimegalencephaly-Polydactyly | |
| 218010 | R | Hernandez (1985) Cortical Blindness; Polydactyly; Mental Retardation | |
| 604211 | R | Hirschsprung Disease with Heart Defects, Laryngeal Anomalies, and Preaxial Polydactyly | |
| 235740 | R | Hirschsprung Disease with Polydactyly, Renal Agenesis, and Deafness | |
| 235750 | R | Hirschsprung Disease with Ulnar Polydactyly, Polysyndactyly of Big Toes, and Ventricular Septal Defect | |
| * | U | Ho (1975) Cleft Palate; Congenital Heart Disease; Absent Tibia; Polydactyly | |
| * | U | Holmes-Schimke-Microcephaly; CHD; Skeletal Abnormalities | |
| 610829 | D | Holprosencephaly 9 | GLI2 |
| 142900 | D | Holt-Oram Syndrome | TBX5 |
| 236110 | R | Holzgreve Syndrome | |
| * | R | Huang (1999) Hirschsprung, Congenital Heart Defect, Laryngeal Anomalies | |
| 236680 | R | Hydrolethalus Syndrome 1 | HYLS1 |
| 215140 | R | Hydrops-Ectopic Calcification-Moth-Eaten Skeletal Dysplasia | LBR |
| 146160 | D | Hypomelia with Müllerian Duct Anomalies | |
| * | M | Hypoplastic Left Heart-Postaxial Polydactyly | |
| * | U | Johnson (1974) Glossopalatine Ankylosis; Cataracts; Abnormal Digits | |
| 147770 | U | Johnson Neuroectodermal Syndrome | |
| 213300, 300804, 608091, 611560 | M | Joubert Syndrome; JBTS | CXORF5, INPP5E, TMEM216, RPGRIP1L |
| * | U | Kantaputra (2003) Symphalangism; Multiple Frenula; Polydactyly; Dental Anomalies | |
| 149000 | D | Klippel-Trenaunay-Weber Syndrome | |
| 606242 | R | Kondoh (2001) Microcephaly-growth Retardation-Atopic Dermatitis-Mental Retardation | |
| * | R | Kozlowski-Krajewska-Polydactyly-Brachydactyly-Uncombable Hair-Mental Retardation | |
| 149730 | D | Lacrimoauriculodentodigital Syndrome | FGFR2, FGFR3, FGF10 |
| ** | R | Lambotte (1990) Microcephaly, Large Ears, Polydactyly, Hypoplastic Thumb | |
| * | U | Lampert (1984)-Craniostenosis; Polydactyly | |
| * | U | Landy-Donnai-Split Hand; Hydrops; Renal Anomalies | |
| * | U | Laryngomalacia-Plus | |
| 607330 | R | Lathosterolosis | SC5DL |
| 135750 | D | Laurin-Sandrow Syndrome | |
| 309800 | X | Lenz Microphthalmia | |
| 163200 | U | Linear Nevus Sebaceous Syndrome | |
| 605944 | R | Liver Fibrocystic Disease and Polydactyly | |
| 602501 | U | Macrocephaly-Capillary Malformation | |
| * | U | Mandibulofacial Dysostosis-Type Guion-Almeida | |
| * | U | Mardini (1985) Lung Agenesis; Congenital Heart Disease; Thumb Anomalies | |
| * | D | Martin-Gorski-Ocular Malformations-polydactyly-membranous Bone Abnormal | |
| 600384 | D | Martinez-Frias (1995) Distal Aphalangia; Syndactyly; Microcephaly | |
| * | U | Martsolf (1977) Skeletal Dysplasia; Polydactyly; Pierre Robin | |
| * | U | McGaughran (1998) Micrognathia-Syndactyly | |
| 246000 | R | McKusick (1968) Cataract; Unilateral Limb Defects | |
| 236700 | R | McKusick-Kaufman Syndrome | MKKS |
| 249000, 603194, 607361, 611134, 611561, 612284 | R | Meckel Syndrome | CC2D2A, CEP290, MKS1, TMEM67, RPGRIP1L |
| 603387 | R | Megalencephaly Polymicrogyria-Polydactyly Hydrocephalus Syndrome | |
| 249310 | R | Megalocornea-Mental Retardation Syndrome | |
| * | U | Meningocoele-Renal Dysplasia-Postaxial Polydactyly | |
| 249620 | R | Mental Retardation, Congenital Heart Disease, Blepharophimosis, Blepharoptosis and Hypoplastic Teeth | |
| 610156 | R | Mental Retardation, Truncal Obesity Retinal Dystrophy, and Micropenis | INPP5E |
| 251255 | R | Microcephaly with Mental Retardation and Digital Anomalies | |
| 601420 | U | Microcephaly, Corpus Callosum Dysgenesis, and Cleft Lip/Palate | |
| 206920 | R | Microphthalmia with Limb Anomalies | |
| 607932 | D | Microphthalmia, Syndromic 6 | BMP4 |
| * | R | Mildenberger (1998) Diffuse Mesangial Sclerosis-Dandy-Walker-polydactyly | |
| 606850 | U | Mirror-Image Polydactyly | MIPOL1 |
| 157900 | M | Moebius | |
| 252100 | R | MOHR Syndrome | |
| * | U | Morava (2004) Focal Skin Defect-Microphthalmia-Limb Defects | |
| * | R | Morton (1998) Lethal Skeletal Dysplasia-Ectopic Digits | |
| 235255 | R | Müllerian Derivatives Persistence of, with Lymphangiectasia and Postaxial Polydactyly | |
| * | R | Multiple Maternal Hypomethylation Syndrome | |
| 312150 | X | Multiple Pterygium Syndrome, X-Linked | |
| 601076 | U | MURCS | |
| 154400 | D | Nager Acrofacial Dysostosis | |
| * | U | Neural Tube Defect-Preaxial Polydactyly-Vertebral Anomalies | |
| 256690 | R | Neuro-Facio-Digito-Renal Syndrome | |
| * | U | NevusComedonicus Syndrome | |
| 251260 | R | Nijmegen Immunodeficiency Syndrome | NBN |
| * | U | Occult Toe | |
| 164200 | D | Oculo-dento-digital Syndrome | GJA1 |
| 273400 | R | Odontotrichomelic Syndrome | |
| 258040 | U | OEIS | |
| 258200 | R | Oliver Syndrome | |
| 106995 | D | Onychonychia-Acral Defects-Cooks | SOX9 |
| * | U | Opitz (1989) Mandibulofacial Dysostosis; Hexadactyly; Lymphoedema | |
| * | U | Oral-Facial-Digital Syndrome-Cerebral Dysgenesis | |
| 612913 | U | Oral-Facial-Digital Syndrome-Type Gabrielli | |
| * | U | Oral-Facial-Digital Syndrome-Type Stenram | |
| * | U | Oral-Facial-Digital Syndrome-Type XII | |
| 311200 | X | Oral-Facial-Digital Syndrome Syndrome I; OFD1 | CXORF5 |
| 258850 | R | Oral-Facial-Digital Syndrome Syndrome III; OFD3 | |
| 258860 | R | Oral-Facial-Digital Syndrome Syndrome IV; OFD4 | |
| 258865 | R | Oral-Facial-Digital Syndrome Syndrome IX; OFD9 | |
| 174300 | D | Oral-Facial-Digital Syndrome Syndrome V; OFD5 | |
| 277170 | R | Oral-Facial-Digital Syndrome Syndrome VI; OFD6 | |
| 300484 | X | Oral-Facial-Digital Syndrome Syndrome VIII; OFD8 | |
| 165590 | D | Oral-Facial-Digital Syndrome Syndrome X; OFD10 | |
| 217085 | R | Orstavik (1992) Oral-Cardiac-Digital Syndrome | |
| * | U | Osteochondrodysplasia-Osteopenia-Preaxial Polydactyly | |
| 304120 | X | Otopalatodigital Syndrome, Type II | FLNA |
| 146510 | D | Pallister-Hall Syndrome; PHS | GLI3 |
| * | R | Panigrahi (2002) Ptosis Polydactyly Mental Retardation | |
| * | U | Parentin-Perissutti Single Incisor-Duane-Bifid Thumb | |
| * | U | Pavone (1991) Connective Tissue Disorder; Polydactyly | |
| * | U | Percin and Percin (2003) An Unusual Syndactyly | |
| * | R | Peters’ Anomaly-Microphthalmia-Arhinia | |
| * | U | Pfeiffer-Angerstein-Bowing-Bone Dysplasia | |
| * | R | Pfeiffer-Mayer-Coloboma; Polydactyly; Mental Retardation | |
| 607539 | R | Phadke (1999) Complex Camptopolydactyly | |
| * | U | Piepkorn (1977) Short Ribs; Polydactyly | |
| * | U | Polydactyly-Colobomata-Hypopituitarism-Cleft Palate | |
| * | U | Polydactyly-Palmar Type | |
| * | U | Polydactyly-Panfollicular Nevus | |
| * | U | Polydactyly-Renal Vascular Malformation | |
| * | U | Polydactyly-Obstructive Uropathy | |
| 174200, 263450, 602085, 607324, 608562 | M | Polydactyly, Postaxial | GLI3 |
| 263540 | U | Polydactyly, Postaxial, with Dental and Vertebral Anomalies | |
| 174310 | D | Polydactyly, Postaxial, with Progressive Myopia | |
| 174400 | D | Polydactyly, Preaxial I | |
| 174500 | D | Polydactyly, Preaxial II; PPD2 | SHH ZRS |
| 174600 | D | Polydactyly, Preaxial III | |
| 174700 | D | Polydactyly, Preaxial IV | GLI3 |
| * | U | Polymetatarsia-Without Polydactyly. | |
| * | U | Polysyndactyly-Delta Phalanges | |
| 263630 | R | Polysyndactyly with Cardiac Malformation | |
| 175690 | D | Polysyndactyly, Crossed | |
| 263750 | R | Postaxial Acrofacial Dysostosis | DHODH |
| 176240 | D | Postaxial Oligodactyly, Tetramelic | |
| * | U | Postaxial Polydactyly-Atrium Anomaly | |
| * | U | Postaxial Polydactyly-Single Atrium-Mental Retardation | |
| 176305 | D | Preaxial Deficiency Postaxial Polydactyly, and Hypospadias | HOXA13 |
| 264480 | R | Pseudotrisomy 13 Syndrome | |
| 147750 | D | Radial Defects-Deafness (IVIC) | |
| 300233 | X | Radioulnar Synostosis-Radial Ray Anomalies | |
| 612095 | R | Reinitis Pgmentosa 41 | PROML1 |
| 266910 | R | Renal Dysplasia; Limb Defects | |
| 208540 | R | Renal-Hepatic-Pancreatic Dysplasia | NPHP3 |
| * | M | Rhombencephalosynapsis | |
| * | U | Rippberger (1976) BBB-like Syndrome with Brachydactyly | |
| 180700 | D | Robinow Syndrome | ROR2 |
| 180750 | D | Robinow-Sorauf Syndrome | TWIST |
| 180849 | D | Rubinstein-Taybi Syndrome | CBP |
| 101120 | U | Sakati-Nyhan-Acrocephalopolysyndactyly Type III | |
| * | U | Say (1987) Clover-leaf Skull; Skeletal Dysplasia | |
| 181250 | U | Scalp Defects and Postaxial Polydactyly | |
| 269150 | R | Schinzel-Giedion Midface-Retraction Syndrome | SETBP1 |
| 179250 | D | Schmitt Hypoplastic Radius, Hypospadias, Maxillary Diastema | |
| * | R | Sener (1990) Synpolydactyly | |
| * | U | Shepherd (1989) Noonan-like Syndrome | |
| * | U | Short Rib-polydactyly Syndrome (Kannu-Aftimos) | |
| 263530 | R | Short Rib-Polydactyly Syndrome, Type I | |
| 263520 | R | Short Rib-Polydactyly Syndrome, Type II | |
| 263510 | R | Short Rib-Polydactyly Syndrome, Type III | DYNC2H1 |
| 269860 | R | Short Rib-Polydactyly Syndrome, Type IV | |
| 300263 | X | Siderius X-Linked Mental Retardation Syndrome | PHF8 |
| 312870 | X | Simpspn-Golabi-Behmel Syndrome, Type I | GPC3 |
| * | D | Sinha-Verma-Postaxial and Mesoaxial Polydactyly | |
| * | U | Situs Inversus-Polydactyly-Broad Thumbs | |
| * | R | Sjogren-Larsson-Like Syndrome with Bone Dysplasia | |
| 270400 | R | Smith-Lemli-Opitz Syndrome | DHCR7 |
| 600095 | D | Split-Hand/Foot Malformation | |
| 272460 | R | Spondylocaroptarsal Synostosis Syndrome | FLNB |
| * | U | Spondylocostal Dysostosis-Preaxial Polydactyly | |
| 277300 | R | Spondylocostal Dysostosis | DLL3 |
| * | U | Stoll-Gasser-Hepatic Ductal Plate Anomalies; Digital Anomalies; Congenital Heart Disease | |
| * | U | Sugiura-Lenz (1999) Polysyndactyly | |
| * | U | Sulko (2010) Tibial Hemimelia-Preaxial Polydactyly-Heart Defects | |
| 186350 | D | Syndactyly-Polydactyly-Earlobe Syndrome | |
| 186200 | D | Syndactyly, Type IV | SHH ZRS |
| 186000 | D | Synpolydactyly 1; SPD1 | HOXD13 |
| 608180 | D | Synpolydactyly 2; SPD2 | FBLN1 |
| * | D | Tabatznik Syndrome | |
| * | U | Tarhan (2004) Mental Retardation, Polysyndactyly, Deafness, Facial Dysmorphism | |
| 608028 | U | Thai Symphalangism Syndrome | |
| 187600 | D | Thanatophoric Dysplasia, Type I | FGFR3 |
| * | U | Thumb Hypoplasia-Preaxial Toe Polydactyly | |
| 601027 | R | Tibia, Absence of Hypoplasia of, with Polydactyly, Retrocerebellar Arachnoid Cyst, and Other Anomalies | |
| 188740 | U | Tibia, Absence of, with Polydactyly | |
| 188770 | D | Tibia, Hypoplasia of, with Polydactyly | |
| 119100 | D | Tibial Aplasia Ectrodactyly Syndrome | |
| 275220 | M | Tibial Hemimelia | |
| * | D | Tibial Hemimelia-Polydactyly-Club Foot | PITX1 |
| * | U | Tollner (1981) Polydactyly; Visceral Anomalies | |
| 107480 | D | Townes-Brocks Syndrome | SALL1 |
| * | U | Triangular Thumb Epiphysis-Angulation Deformity | |
| 190600 | D | Triphalangeal Thumb, Nonopposable | |
| 190650 | D | Triphalangeal Thumbs and Dislocation of Patella | |
| 190680 | D | Triphalangeal Thumbs with Brachyectrodactyly Ulna and Fibula, Absence of, with Severe Limb | |
| 276820 | R | Deficiency | WNT7A |
| 276821 | R | Ulnar Hypoplasia with Mental Retardation | |
| 604380 | M | Ulnar Ray Dysgenesis with Postaxial Polydactyly and Renal Cystic Dysplasia | |
| 181450 | D | Ulnar-Mammary Syndrome | TBX3 |
| 268250 | R | Urbach (1986) Skeletal Dysplasia; Rhizomelia of Humeri | |
| * | R | Urioste (1996) Limb Deficiency-Vertebral Hypersegmentation-Absent Thymus | |
| * | U | VACTERL Association-Tibial Aplasia | |
| 192350 | U | VATER Association | |
| 608406 | R | VATER-Like Defects with Pulmonary Hypertension, Laryngeal Webs, and Growth Deficiency | |
| 277590 | U | Weaver Syndrome | NSD1 |
| 193530 | D | Weyers Acrofacial Dysostosis | EVC |
| * | U | Wieczorek (2002) Thumb Aplasia-Radial Aplasia-Microcephaly | ZBTB16 |
| * | U | Wiedemann (1985c) Macrocephaly; Polydactyly of Toes; Tibial Defect | |
| * | U | Wolter (1971) Papilla Nigra; Cleft Palate; Extra Thumb | |
| 194350 | D | WT Syndrome-Pancytopenia-Hand Defects | |
| * | D | Zannolli (2008) Polydactyly-Ectodermal Dysplasia |
Indicates that the entry was sourced from the Winter-Baraitser Dysmorphology Database,
Indicates that the entry was sourced from the Stevenson et al text {Stevenson, 2006 #1688}, D: Autosomal dominant inheritance, R: Autosomal recessive inheritance, X: Sex-linked Inheritance, M: Multiple modes of inheritance, U: Unknown inheritance. Highlighted clinical entities are non-syndromic.
Among the 310 entities, 80 have been associated with causative mutations in a total of 99 genes. This represents major progress, as the 2002 analysis identified only 39 entities associated with mutations. As before, these disorders illustrate another prominent feature, which is that of genocopies and pleiotropism. First, there are a number of entities that can be caused by mutations in more than one gene (genocopies). Among the entries with identified mutations, Fanconi anemia can be caused by homozygous or compound heterozygous mutations in one of 14 genes and Bardet-Beidl syndrome can be caused by mutations in at least 12 genes. These two disorders alone account for 26 of the 99 genes known to cause polydactyly when mutated. The remaining 308 entries are associated with mutations in 73 genes (note that MKKS is counted in both categories because distinct mutations in that gene can cause either McKusick-Kaufman syndrome or Bardet-Biedl syndrome). These 73 genes are associated with 95 distinct clinical entities, which is an expression of the concept of pleiotropy. A major culprit in this pleiotropy is the GLI3 transcription factor gene, which can be attributed to five phenotypes [Elson et al., 2002; Kang et al., 1997; Radhakrishna et al., 1999; Radhakrishna et al., 1997; Vortkamp et al., 1991]. In the 2002 review, there were three genes associated with two phenotypes each: MKKS, EVC, and DHCR7 [Cormier-Daire et al., 1996; Katsanis et al., 2000; Ruiz-Perez et al., 2000; Slavotinek et al., 2000; Stone et al., 2000; Wassif et al., 1998]. At the time of the present analysis, the Rutledge lethal multiple congenital anomaly syndrome, associated with DHCR7 mutations, has been collapsed into Smith-Lemli-Opitz syndrome because it was determined that the two, previously considered distinct entities, actually formed a continuous spectrum of phenotype. As of the present review, there are 15 sets of multiple phenotypic entities that have been shown to be caused by mutations in a single gene (Table II).
Table II.
Genes that, when mutated, can cause more than one clinically distinct phenotype in humans
| Gene | Clinical Entity |
|---|---|
| CD96 | C syndrome C-like syndrome |
| CXORF5 | Joubert syndrome* Oral-facial-digital syndrome type I |
| DYNC2H1 | Asphyxiating thoracic dystrophy type 3 Short-Rib polydactyly syndrome |
| EVC | Ellis-Van Creveld syndrome Weyers acrofacial dysostosis |
| FBLN1 | De Smet complex synpolydactyly Synpolydactyly* |
| FGFR2 | Apert syndrome Lacrimoauriculodentodigital syndrome |
| FLNB | Atelosteogenesis type III Spondylocarpotarsal dysostosis |
| GDF5 | Brachydactyly type C Chondrodysplasia, Grebe type |
| GLI3 | Greig cephalopolysyndactyly syndrome Pallister-Hall syndrome Acrocallosal syndrome Polydactyly, postaxial Polydactyly, preaxial* |
| INPP5B | Joubert syndrome* Mental retardation, truncal obesity, retinal dystrophy, and micropenis |
| MKKS | Bardet-Biedl syndrome McKusick-Kaufman syndrome |
| ROR2 | Brachydactyly type B Robinow syndrome |
| RPGRIP1L | Joubert syndrome* Meckel Syndrome |
| SHH** | Polydactyly, preaxial* Synpolydactyly* |
| WNT7A | Fibular a/hypoplasia, femoral bowing and poly-, syn-, and oligodactyly Ulna and fibula, absence of, with severe limb deficiency |
Note that these phenotypes can be caused by mutations in more than one of the genes listed in the left column.
Note that these mutations are in the SHH ZRS (ZPA regulatory sequence) and not in the SHH gene proper.
These results illustrate a number of important principles of clinical medicine, medical diagnosis, and the taxonomy of disease. The boundaries that delineate and demarcate disorders from other disorders can be difficult to determine. Essentially all human pleiotropic developmental anomaly syndromes overlap to a small, or sometimes large, extent with one or more other syndromes. It is not always possible to define unambiguous phenotypic categories and therefore there is debate about the boundaries of clinical entities. As noted above, it can also be difficult to rigorously distinguish syndromic from non-syndromic phenotypes. In the 1980’s it was presumed that molecular diagnosis would solve these problems. In fact, an unsupported, but commonly held aphorism in those times was “one gene – one disease”. A large body of work has overthrown that naïve view and we now recognize that the relationship of genotype and phenotype is much more complex and nuanced. An example of this is the situation with the McKusick-Kaufman and Bardet-Biedl syndromes. The McKusick-Kaufman syndrome comprises polydactyly, congenital heart disease, and hydrometrocolpos (obstruction secondary to imperforate uterovaginal plate) in females and hypospadias in males [Slavotinek and Biesecker 2000]. This phenotype is almost entirely limited to the Old Order Amish with ancestors in Southeastern Pennsylvania and is caused by a homozygous double mutation in the MKKS gene (homozygous c.[726C>G + 250C>T], p.[Ala242Ser + His84Tyr]) [Stone et al., 2000]. In contrast, all other homozygous or compound heterozygous mutations in MKKS cause the Bardet-Biedl syndrome (polydactyly, pigmentary retinal dystrophy, obesity, intellectual disability, hypogonadism, and other anomalies) [Katsanis et al., 2000; Slavotinek et al., 2000]. Although these two phenotypes can overlap in childhood, the adult manifestations are readily distinguished and the consequences for the patients are markedly distinct. In addition, the phenotypes breed true – that is, families with true McKusick-Kaufman syndrome do not have members affected with Bardet-Biedl syndrome and vice versa. They are therefore considered to be distinct clinical entities. To further complicate the situation, it is now known that Bardet-Biedl syndrome can be caused by mutations in at least 11 genes in addition to MKKS. This is an example of how mutations in one gene can cause more than one phenotype (as shown in Table II) and mutations in more than one gene can apparently cause a single phenotype (e.g., Table I entries for Bardet-Biedl or Fanconi syndromes). This means that the genetic etiology alone cannot completely solve the diagnostic challenges that clinicians face, although they can be extremely helpful in confirming or eliminating diagnoses and narrowing the list of potential disorders that the clinician must consider.
The classes of genes products can be interpreted as a reflection of categories of genes that are important in mammalian development. Whereas transcription factors were the largest group in the prior analysis, the current gene list is dominated by genes that encode proteins involved in cell signaling (21 genes) and genes that encode for proteins in the basal body and cilium (13 genes). The other major categories of gene products implicated in phenotypes associated with polydactyly are the DNA repair genes (15 genes, primarily attributable to the Fanconi anemia phenotypes), followed by the transcription factors (16 genes). Much less commonly involved (fewer than 5 identified) genes encode structural proteins, catalytic proteins, immunoglobulin superfamily proteins, chaperones, and gap junctions. This significant shift in the distribution of identified genes since 2002 reflects the rapidly increasing emphasis on signaling pathways in development [Duboc and Logan 2009] and the key role of the cilium and basal body in the Sonic hedgehog-GLI3 transcription factor pathway [Goetz and Anderson 2010].
Perspectives and Future Directions
From the data reviewed above, it is clear that a great deal of progress has been made in elucidating the etiology of polydactyly since the previous review in 2002. Recent technologic developments, especially that of massively parallel sequencing [Shendure and Ji 2008], have shown remarkable initial promise to accelerate the process of gene identification in rare disorders. The coupling of massively parallel sequencing to various implementations of target selection [Gnirke et al., 2009] to enrich DNA samples for protein-coding exons, has been shown to be effective for mutation detection. Several disorders have recently been elucidated by various implementations of this technology including Miller syndrome [Ng et al., 2010] and TARP syndrome [Johnston et al., 2010]. These technologies accelerate human genetic discovery because they have the capability not only to increase sequence acquisition, but to potentially bypass meiotic mapping, which can be limiting in ultra rare disorders. As many of the disorders in Table I that have not yet been associated with mutations in a gene are known to occur in only a few or even in single families, this technologic advance holds out the promise of elucidating the etiology of most, if not nearly all of these disorders. Therefore, one can anticipate that human geneticists will, in the next several years, have a catalog of nearly all of the genes that are mutated in patients with polydactyly phenotypes, thus comprising a rich catalog of pathologic variations as well as a large list of genes important in anterior-posterior patterning in the limb. One can readily imagine that massively parallel sequencing of transcripts in developing limbs will delineate another set of genes, and that these sets can be analyzed and intersected to develop a rich, and perhaps nearly complete catalog of genes important for the patterning of the limb. With this knowledge, one can further predict that developmental biologist will have the resources to characterize the key pathways in the development of the limb in humans and in model systems, which can be used to develop regenerative or cell replacement therapies for limb anomalies.
Footnotes
These data were presented at the 6th International Limb Development and Regeneration Conference in Williamsburg, Virginia, USA, July 16, 2010.
Online sources: Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim
References
- Allanson JE, Biesecker LG, Carey JC, Hennekam RC. Elements of morphology: introduction. American Journal of Medical Genetics Part A. 2009;149A:2–5. doi: 10.1002/ajmg.a.32601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anonymous. Online Mendelian Inheritance in Man, OMIM (TM) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University; Baltimore, MD: National Center for Biotechnology Information, National Library of Medicine; Bethesda, MD: 2010. [Google Scholar]
- Biesecker LG. Polydactyly: how many disorders and how many genes? American Journal of Medical Genetics. 2002;112:279–283. doi: 10.1002/ajmg.10779. [DOI] [PubMed] [Google Scholar]
- Biesecker LG. Mapping phenotypes to language: a proposal to organize and standardize the clinical descriptions of malformations. Clinical Genetics. 2005;68:320–326. doi: 10.1111/j.1399-0004.2005.00509.x. [DOI] [PubMed] [Google Scholar]
- Biesecker LG. What you can learn from one gene: GLI3. J Med Genet. 2006;43:465–469. doi: 10.1136/jmg.2004.029181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butterfield NC, McGlinn E, Wicking C. The molecular regulation of vertebrate limb patterning. Curr Top Dev Biol. 2010;90:319–341. doi: 10.1016/S0070-2153(10)90009-4. [DOI] [PubMed] [Google Scholar]
- Cormier-Daire V, Wolf C, Munnich A, Le Merrer M, Nivelon A, Bonneau D, Journel H, Fellmann F, Chevy F, Roux C. Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz and the lethal acrodysgenital syndromes. Eur J Pediatr. 1996;155:656–659. doi: 10.1007/BF01957147. [DOI] [PubMed] [Google Scholar]
- Duboc V, Logan MP. Building limb morphology through integration of signalling modules. Curr Opin Genet Dev. 2009;19:497–503. doi: 10.1016/j.gde.2009.07.002. [DOI] [PubMed] [Google Scholar]
- Elson E, Perveen R, Donnai D, Wall S, Black GC. De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. J Med Genet. 2002;39:804–806. doi: 10.1136/jmg.39.11.804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol. 2009;27:182–189. doi: 10.1038/nbt.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goetz SC, Anderson KV. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010;11:331–344. doi: 10.1038/nrg2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnston JJ, Teer JK, Cherukuri PF, Hansen NF, Loftus SK, Chong K, Mullikin JC, Biesecker LG. Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. American Journal of Human Genetics. 2010;86:743–748. doi: 10.1016/j.ajhg.2010.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones KL, Smith DW. Smith’s recognizable patterns of human malformation. xviii. Philadelphia: Elsevier Saunders; 2006. p. 954. [Google Scholar]
- Kang S, Graham JM, Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature Genetics. 1997;15:266–268. doi: 10.1038/ng0397-266. [DOI] [PubMed] [Google Scholar]
- Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson WS, Lupski JR. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet. 2000;26:67–70. doi: 10.1038/79201. [DOI] [PubMed] [Google Scholar]
- Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics. 2010;42:30–35. doi: 10.1038/ng.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Radhakrishna U, Bornholdt D, Scott H, Patel U, Rossier C, Engel H, Bottani A, Chandal D, Blouin J, Solanki J, Grzeschik K, Antonarakis S. The phenotypic spectrum of GLI3 morphopathies includes autsomal dominant polydactyly type IV and postaxial polydactyly type A/B; no phenotype prediction from the position of GLI3 mutations. American Journal of Human Genetics. 1999;65:645–655. doi: 10.1086/302557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Radhakrishna U, Wild A, Grzeschik K-H, Antonarakis SE. Mutation in GLI3 in post-axial polydactyly type A. Nature Genetics. 1997;17:269–270. doi: 10.1038/ng1197-269. [DOI] [PubMed] [Google Scholar]
- Robin NH, Biesecker LG. Considerations for a multiaxis nomenclature system for medical genetics. Genet Med. 2001;3:290–293. doi: 10.1097/00125817-200107000-00004. [DOI] [PubMed] [Google Scholar]
- Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, King L, Francomano C, Freisinger P, Spranger S, Marino B, Dallapiccola B, Wright M, Meitinger T, Polymeropoulos MH, Goodship J. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000;24:283–286. doi: 10.1038/73508. [DOI] [PubMed] [Google Scholar]
- Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26:1135–1145. doi: 10.1038/nbt1486. [DOI] [PubMed] [Google Scholar]
- Slavotinek AM, Biesecker LG. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review. Am J Med Genet. 2000;95:208–215. [PubMed] [Google Scholar]
- Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, Musarella MA, Parfrey PS, Sheffield VC, Biesecker LG. Mutations in MKKS cause Bardet-Biedl syndrome. Nature Genetics. 2000;26:15–16. doi: 10.1038/79116. [DOI] [PubMed] [Google Scholar]
- Stevenson RE. Human malformations and related anomalies. xiv. Oxford; New York: Oxford University Press; 2006. p. 1495. [Google Scholar]
- Stone DL, Slavotinek AS, Bouffard GG, Banerjee-Basu S, Baxevanis AD, Barr M, Biesecker LG. Mutations of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nature Genetics. 2000;25:79–82. doi: 10.1038/75637. [DOI] [PubMed] [Google Scholar]
- Towers M, Tickle C. Growing models of vertebrate limb development. Development. 2009;136:179–190. doi: 10.1242/dev.024158. [DOI] [PubMed] [Google Scholar]
- Vortkamp A, Gessler M, Grzeschik K-H. GLI3 zinc finger gene interrupted by translocations in Greig syndrome families. Nature. 1991;352:539–540. doi: 10.1038/352539a0. [DOI] [PubMed] [Google Scholar]
- Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, Steiner RD, Porter FD. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998;63:55–62. doi: 10.1086/301936. [DOI] [PMC free article] [PubMed] [Google Scholar]