Postaxial Polydactyly Type Research Articles

A novel homozygous FAM92A gene (CIBAR1) variant further confirms its association with non-syndromic postaxial polydactyly type A9 (PAPA9).

Polydactyly is a very common digit anomaly, having extra digits in hands and/or toes. Non-syndromic polydactyly in both autosomal dominant and autosomal recessive forms are caused by disease-causing variants in several genes, including GLI1, GLI3, ZNF141, FAM92A, IQCE, KIAA0825, MIPOL1, STKLD1, PITX1, and DACH1. Whole exome sequencing (WES) followed by bi-directional Sanger sequencing was performed for the single affected individual (II-1) of the family to reveal the disease causative variant/gene. 3D protein modeling and structural molecular docking was performed to determine the effect of the identified mutation on the overall protein structure. WES revealed a novel biallelic missense variant (c.472G>C; p.Ala158Pro) in exon 6 of the FAM92A gene. The identified variant segregated perfectly with the disease phenotype using Sanger sequencing. Furthermore, Insilco analysis revealed that the variant significantly changes the protein secondary structure, and substantially impact the stability of FAM92A. We report the second FAM92A disease-causing mutation associated with recessive non-syndromic postaxial polydactyly. The data further confirms the contribution of FAM92A in limb development and patterning.

Rare Occasion of Congenital Anomalies: Bilateral Syndactyly with Multiple Polydactyly of the Hands and Feet

Introduction: Upper and lower limb malformations are essential things that occur related to congenital disabilities, including syndactyly and polydactyly. It may appear in association with other birth defects as a part of a syndrome and may be present in the upper extremity or lower extremity. Cases of bilateral syndactyly with multiple polydactyly of the hands and feet are the first time in our center, and they must be promptly diagnosed and treated to avoid functional and cosmetic problems. Case presentation: A 3-month-old male toddler presented with webbed index, middle, and ring fingers with synonichia, accompanied by additional fingers on hands and feet. An x-ray examination revealed preaxial polydactyly at both hands with bifid phalanx (Wassel classification) and postaxial polydactyly type B. Duplicated postaxial metatarsal (Venn-Watson classification) and type B postaxial polydactyly also occur on both feet with webbed index and middle toe on the left foot. Direct closure was achieved with a dorsal trapezoidal and zig-zag flap to release the second and third fingers of the right hand, followed by resection of rudimentary fingers to help the child with early stages of motoric functions. Discussion: Syndactyly can cause a length difference that results in growth and functional difficulties. Surgical release of the index to middle and middle to ring fingers should be done early between 3-6 months of age and is expected to help the child grasp, write, and subsequently manipulate objects. We prioritize operating the right hand as around 90% of people prefer to use the right hand. Simple ligation was also performed to recess the rudimentary fingers on both hands and feet. It has no functional benefit and can limit function as it may get caught or make it difficult to wear shoes and gloves. We have to remind the parents that multiple surgeries may be necessary to achieve a satisfactory result and to complete the reconstruction before 24 months of age when the patterns of function of the digits are established. Conclusion: Bilateral complex syndactyly with preaxial and postaxial polydactyly on both hands and feet are distinctly uncommon entities that need multidisciplinary treatment. In this instance, the syndactyly releasing of the second and third fingers on the right hand is prioritized based on the function to be achieved, with excision of the rudimentary fingers.

A biallelic variant in IQCE predisposed to cause non-syndromic post-axial polydactyly type A

Background: Polydactyly or hexadactyly is a familiar limb defect that either occurs as an isolated entity (non-syndromic) or is associated with severe (syndromic) morphological phenotypes. Generally, it appears due to a defect in the anteroposterior patterning during limb development. Methods: Here, we present a proband having non-syndromic post-axial polydactyly (PAP) evaluated using whole exome sequencing followed by Sanger sequencing. Furthermore, 3D protein modeling was executed for the normal and mutated IQ domain-containing protein E (IQCE) gene. Results: WES analysis revealed an already reported bi-allelic variant (c.395-1 G>A) in the IQCE gene, previously associated with PAP 7. Furthermore, 3D modeling revealed significant fluctuations in the IQCE protein secondary structure, thus affecting downstream signaling. Conclusion: The work presented validated the significant role of the IQCE gene in the development and patterning of human limbs.

Structural Evaluation and Conformational Dynamics of ZNF141T474I Mutation Provoking Postaxial Polydactyly Type A.

This study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.1420C > T; p.T474I) in ZNF141 gene segregating PAP through a molecular dynamics simulations approach. In ZNF141 protein, helices play a crucial role by attaching three specific target DNA base pairs. In ZNF141T474I protein, H1, H3, and H6 helices attain more flexibility by acquiring loop conformation. The outward disposition of the proximal portion of H9-helix in mutant protein occurs due to the loss of prior beta-hairpins at the C terminal region of the C2-H2 domain. The loss of hydrogen bonds and exposure of hydrophobic residues to solvent and helices turning to loops cause dysfunction of ZNF141 protein. These significant changes in the stability and conformation of the mutant protein were validated using essential dynamics and cross-correlation maps, which revealed that upon point mutation, the overall motion of the proteins and the correlation between them were completely different, resulting in Postaxial polydactyly type A. This study provides molecular insights into the structural association of ZNF141 protein with PAP type A. Identification of active site residues and legends offers new therapeutic targets for ZNF141 protein. Further, it reiterates the functional importance of the last residue of a protein.

Current Treatment and Billing Trends of Postaxial Polydactyly Type B.

Current Treatment and Billing Trends of Postaxial Polydactyly Type B.

Prenatal Detection of Novel Compound Heterozygous Splice Site Variants of the KIAA0825 Gene in a Fetus with Postaxial Polydactyly Type A.

Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found by fetal ultrasonography. To better evaluate fetal prognosis, SNP array analysis and trio whole-exome sequencing (trio-WES) were performed to identify the underlying etiology. Although SNP array analysis revealed no abnormality, trio-WES identified compound heterozygous splice site variants in KIAA0825, c.-1-2A>T and c.2247-2A>G in intron 2 and intron 12, respectively. These two splice site variants were absent in control databases and were predicted to influence splicing by in silico analysis. To confirm the potential pathogenicity of the variants, in vitro splicing assays using minigene and RNA from peripheral leukocytes of the heterozygous parents were conducted. Minigene and RT-PCR assays demonstrated that the c.-1-2A>T variant led to the loss of the initiation codon, and the c.2247-2A>G variant mainly resulted in exon 13 skipping. Prenatal WES and subsequent functional studies are important approaches for defining the genetic etiology of fetuses with PAPA and are also essential for accurate genetic counseling and decision making. Taken together, this study expands the spectrum of KIAA0825 variations in PAPA patients and increases the knowledge of the molecular consequences of KIAA0825 splice site variants.

Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A

Polydactyly or hexadactyly is characterized by an extra digit/toe with or without a bone. Currently, variants in ten genes have been implicated in the non-syndromic form of polydactyly.DNA from a single affected individual having bilateral postaxial polydactyly was subjected to whole exome sequencing (WES), followed by Sanger sequencing. Homology modeling was performed for the identified variant and advance microscopy imaging approaches were used to reveal the localization of the DACH1 protein at the base of primary cilia.A disease-causing biallelic missense variant (c.563G > A; p.Cys188Tyr; NM_080760.5) was identified in the DACH1 gene segregating perfectly within the family. Structural analysis using homology modeling of the DACH1 protein revealed secondary structure change that might result in loss of function or influence downstream interactions. Moreover, siRNA-mediated depletion of DACH1 showed a key role of DACH1 in ciliogenesis and cilia function.This study provides the first evidence of involvement of the DACH1 gene in digits development in humans and its role in primary cilia. This signifies the importance and yet unexplored role of DACH1.

Local Anesthesia Alone for Postaxial Polydactyly Surgery in Infants.

Surgical excision for postaxial polydactyly type B is advocated to avoid long-term complications. Excision with local anesthesia (LA) in infancy represents a safe and effective treatment for this condition, although general anesthesia (GA) is employed by many surgeons. We present a comparison of surgical outcomes, cost, and time between LA and GA to support widespread change in management. A retrospective review of patients under 12 months of age undergoing surgical polydactyly excision by a single surgeon was performed. Anesthesia type, patient demographics, and complications were recorded. Comparisons were made between LA and GA groups on procedure cost, operating time, length of stay (LOS), and time from procedure end to discharge. Stepwise forward regression was used to identify the best model for predicting total costs. Ninety-one infants with a mean age of 3 months (±1.9) were examined; 51 (56%) underwent LA alone, 40 (44%) underwent GA. Mean operating time was 11.53 ± 4.36 minutes, with no difference observed between anesthesia groups (P = .39). LA infants had a significantly shorter LOS (2.5 vs 3.5 hours; P < .05), quicker postoperative discharge (32 vs 65 minutes, P < .05), and fewer overall expenses, 2803 vs 6067 U.S. dollars (USD), P < .05. Two minor surgical complications (1 in each group) were reported. This study demonstrates significantly decreased cost, LOS, and time to discharge using LA alone for surgical excision of postaxial polydactyly type B. Results suggest the approach is quick, economical, and avoids the risks of GA in early infancy.

Identification of a novel biallelic missense variant in the KIAA0825 underlies postaxial polydactyly type A

Postaxial polydactyly (PAP) is characterized by development of extra digits, which mostly segregates in autosomal recessive pattern. The underlying genetic cause of recessive non-syndromic PAP type A has been associated with sequence variants in five different genes (ZNF141, IQCE, GLI1, FAM92A, KIAA0825).The present study was aimed to investigate clinical and genetic causes of PAPA in a consanguineous family of Pakistani origin. Microsatellite-based linkage analysis was used to search for the disease-causing gene. Linkage in the family was established at chromosome 5q15 harbouring a candidate gene KIAA0825. Subsequently, Sanger sequencing revealed a novel homozygous missense variant [c.50T>C; p. (Leu17Ser)] in the gene, which co-segregated with the disease within the family. Protein structural analysis predicted a substantial change in the secondary structure of the mutant protein affecting its function. This is the third disease causing variant identified in the KIAA0825. This has not only expanded spectrum of the mutations in the gene but also further substantiated its role in the limb development in human.

A novel missense in GLI3 possibly affecting one of the zinc finger domains may lead to postaxial synpolydactyly: case report

BackgroundPolydactyly is one of the most common congenital hand/foot malformations in humans. Mutations in GLI3 have been reported to cause syndromic and non-syndromic forms of preaxial and postaxial polydactylies.Case presentationThe patient was a 2-year-old boy who underwent surgery in our hospital. The right hand and left foot of the patient were labelled as postaxial polydactyly type B, and there was cutaneous webbing between the 3rd and 4th fingers of the left hand. We identified a novel c. 1622C > T variant in GLI3 leading to an isolated postaxial synpolydactyly.ConclusionsThe patient carries a novel autosomal dominant heterozygous missense mutation. This mutation c.1622C > T;p.(Thr541Met) in the GLI3 gene may affect the normal function of the zinc finger domain (ZFD) in a different way. However, it seems that more research is needed to determine the exact effects of this mutation.

Novel GLI3 Mutations in Chinese Patients with Non-syndromic Post-axial Polydactyly.

Polydactyly, characterized by supernumerary digits in the upper or lower extremities, is the most common congenital digital abnormalities. It derives from the defective patterning of anteroposterior axis of the developing limb, with various etiology and clinical heterogeneity. The patients with post-axial polydactyly type A (PAPA) have the typical symptom of a well-formed supernumerary digit outside the fifth digit. The aim of present study was to identify the causative mutations of two unrelated Han Chinese patients with non-syndromic PAPA. Two unrelated Han Chinese patients and 100 ethnicity-matched, unrelated normal controls were recruited for this study. BGISEQ-500 exome sequencing was performed in the two patients, followed by validation in the patients and 100 controls by using Sanger sequencing. Two mutations in the GLI family zinc finger 3 gene (GLI3), including a frameshift mutation c.3437_3453delTCGAGCAGCCCTGCCCC (p.L1146RfsX95) and a nonsense mutation c.3997C>T (p.Q1333X), were identified in two patients but were absent in the 100 healthy controls. The two GLI3 mutations, p.L1146RfsX95 and p.Q1333X, may account for non-syndromic PAPA in the two patients, respectively. The findings of this study may expand the mutational spectrum of GLI3-PAPA and provide novel insights into the genetic basis of polydactyly.

Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

BackgroundPolydactyly is a common genetic limb deformity characterized by the presence of extra fingers or toes. This anomaly may occur in isolation (nonsyndromic) or as part of a syndrome. The disease is broadly divided into preaxial polydactyly (PPD; duplication of thumb), mesoaxial polydactyly (complex polydactyly), and postaxial polydactyly (PAP: duplication of the fifth finger). The extra digits may be present in one or both the limbs. Heterozygous variants in the GLI3, ZRS/SHH, and PITX1 have been associated with autosomal dominant polydactyly, while homozygous variants in the ZNF141, IQCE, GLI1, and FAM92A have been associated with autosomal recessive polydactyly. Pathogenic mutations in the GLI3 gene (glioma‐associated oncogene family zinc finger 3) have been associated with both nonsyndromic and syndromic polydactyly.MethodsHere, we report an extended five generation kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Whole‐exome sequencing followed by variant prioritization, bioinformatic studies, Sanger validation, and segregation analysis was performed.ResultsUsing exome sequencing in the three affected individuals, we identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of the GLI3 encoding gene.ConclusionTo the best of our knowledge, the present study reports on the first familial case of nonsyndromic postaxial polydactyly due to the GLI3 variant in Pakistani population. Our study also demonstrated the important role of GLI3 in causing nonsyndromic postaxial polydactyly.

Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb.

Polydactyly is characterized by an extra supernumerary digit/toe with or without bony element. To date variants in four genes GLI3, ZNF141, MIPOL1 and PITX1 have been implicated in developing non-syndromic form of polydactyly. The present study involved characterization of large consanguineous family of Pakistani origin segregating post-axial polydactyly type A, restricted to lower limb, in autosomal recessive pattern. DNA of two affected members in the family was subjected to exome sequencing. Sanger sequencing was then followed to validate segregation of the variants in the family members. A homozygous splice acceptor site variant (c.395-1G>A) was identified in the IQCE gene, which completely co-segregated with post-axial polydactyly phenotype within the family. The homozygous variant was absent in different public variant databases, 7000 in-house exomes, 130 exomes from unrelated Pakistani individuals and 215 ethnically matched controls. Mini-gene splicing assay was used to test effect of the variant on function of the gene. The assay revealed loss of first nucleotide of exon 6, producing a -1 frameshift and a premature stop codon 22 bases downstream of the variant (p.Gly132Valfs*22). The study provided the first evidence of involvement of the IQCE gene in limbs development in humans.

Ulnar Polydactyly

Postaxial polydactyly type B (PAPD-B) refers to the nonfunctional, floppy extra digit on the ulnar border of the hand. Suture ligation is applied in the newborn unit if the base is narrow or pedunculated. However, wart-like scars, residual bumps, or neuromas are frequent complications. Wider-based extra digits are treated at a later age by surgical excision under general anesthesia. Surgical clip application expands the indications for PAPD treatment in the newborn unit or outpatient setting with lesser incidences of complications. A retrospective review identified 231 hands with PAPD-B in 132 newborns treated with surgical clips between January 1, 1996, and November 30, 2010, having a minimum of 2 years of follow-up. Medical records were queried for complications, revision procedures, and parent satisfaction. A relative cost survey compares the costs of surgical clips to surgery. In all, 16 extremities in 9 patients (7%) required surgical scar revision. No wound complications were noted.

Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5

Genomic rearrangements at chromosome 13q31.3q32.1 have been associated with digital anomalies, dysmorphic features, and variable degree of mental disability. Microdeletions leading to haploinsufficiency of miR17∼92, a cluster of micro RNA genes closely linked to GPC5 in both mouse and human genomes, has recently been associated with digital anomalies in the Feingold like syndrome. Here, we report on a boy with familial dominant post-axial polydactyly (PAP) type A, overgrowth, significant facial dysmorphisms and autistic traits who carries the smallest germline microduplication known so far in that region. The microduplication encompasses the whole miR17∼92 cluster and the first 5 exons of GPC5. This report supports the newly recognized role of miR17∼92 gene dosage in digital developmental anomalies, and suggests a possible role of GPC5 in growth regulation and in cognitive development.

Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A

BackgroundPostaxial polydactyly (PAP) type A is characterised by well-formed functionally developed 5th digit duplication in hands and/or feet. It is genetically heterogeneous condition, inherited both in autosomal recessive and dominant...

Expanded mutational spectrum of the GLI3 gene substantiates genotype–phenotype correlations

Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister–Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75 %) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52 %), whereas at least one typical dysmorphic feature was manifested in 17 patients (63 %). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7 %). Our findings fully support previous genotype–phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene.

Genetic mapping of an autosomal recessive postaxial polydactyly type A to chromosome 13q13.3–q21.2 and screening of the candidate genes

Postaxial Polydactyly (PAP) is characterized by fifth digit duplication in hands and/or feet. Two types of PAP including PAP-A, representing the development of well-formed extra digit, and PAP-B, representing the presence of rudimentary fifth digit, have been described. Both isolated and syndromic forms of PAP have been reported. Isolated forms of PAP usually segregate as an autosomal dominant trait and to date four loci have been identified. In the present study, we have described mapping of the first locus of autosomal recessive PAP type A on chromosome 13q13.3-13q21.2 in a consanguineous Pakistani family. Using polymorphic microsatellite markers, the disease locus was mapped to a 17.87-cM (21.13 Mb) region flanked by markers D13S1288 and D13S632, on chromosome 13q13.3-13q21.2. A maximum multipoint LOD score of 3.84 was obtained with several markers along the disease interval. DNA sequence analysis of exons and splice-junction sites of ten candidate genes (CHM-I, TSC22D1, FOXO1, DIAPH3, CCDC122, CKAP2, SUGT1, RANKL, LPAR6, C13ORF31) did not reveal potentially causal variants.

Metopic craniosynostosis due to mutations inGLI3: A novel association

We report on the novel association of trigonocephaly and polysyndactyly in two unrelated patients due to mutations within the last third (exon 14) and first third (exon 6) of the GLI3 gene, respectively. GLI3 acts as a downstream mediator of the Sonic hedgehog signal-transduction pathway which is essential for early development; and plays a role in cell growth, specialization, and patterning of structures such as the brain and limbs. GLI3 mutations have been identified in patients with Pallister-Hall, Grieg cephalopolysyndactyly syndrome (GCPS), postaxial polydactyly type A1, preaxial polydactyly type IV, and in one patient with acrocallosal syndrome (ACLS). Furthermore, deletions including the GLI3 gene have been reported in patients with features of GCPS and ACLS. To date, trigonocephaly has not been associated with abnormalities of GLI3 and craniosynostosis is not a feature of GCPS. However, Hootnick and Holmes reported on a father with polysyndactyly and son with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum, considered GCPS thereafter. Guzzetta et al. subsequently described a patient with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum postulating a diagnosis of GCPS, later considered ACLS. In retrospect, these two patients, evaluated prior to mutational analysis, and our patients, with confirmed mutations, likely fall within the GLI3 morphopathy spectrum and may provide a bridge to better understanding those patients with overlapping features of GCPS and ACLS. Based on this observation, we suggest GLI3 studies in patients presenting with this constellation of findings, specifically metopic craniosynostosis with polysyndactyly, in order to provide appropriate medical management and genetic counseling.

An interstitial duplication of chromosome 13q31.3q32.1 further delineates the critical region for postaxial polydactyly type A2

Postaxial polydactyly type A2 (PAP-A2; OMIM 602085) is a common feature seen in patients with a partial duplication of the long arm of chromosome 13. Dose dependency has been shown for digital malformations in this region, deletions resulting in oligodactyly and duplications in polydactyly. We aimed to narrow down the critical region for PAP-A2 in order to identify candidate genes.We performed chromosomal analysis, FISH and array-CGH in a patient with an interstitial duplication of chromosome 13q31.3q32.1 and a mild phenotype including postaxial polydactyly. The duplicated region spanned 5.59 Mb (89.67–95.25 Mb) and contained eleven known genes, including GPC5 and GPC6.GPC5 and GPC6 show homology with GPC3 and GPC4, genes involved in Simpson-Golabi-Behmel syndrome, an overgrowth syndrome in which also polydactyly can occur. Mouse studies have shown expression of both GPC5 and GPC6 in developing limbs. Therefore, we propose that GPC5 and GPC6 are the most likely candidate genes for PAP-A2.