Supernumerary digits, or polydactyly, have been described in various species including humans, wild and domestic animals. In horses, it represents the most common congenital limb malformation, which has only been described in isolated cases or nuclear families. Molecular aetiology has not been reported. To characterise the phenotype of a non-syndromic pre-axial polydactyly in a horse family and to decipher the inheritance pattern. Retrospective study. Forty-three members of the family including a previously reported polydactyl case were recruited. Available clinical and radiographical findings from the initial case and its family members were summarised and karyotypic examinations of the horses were performed. On clinical examination, eight horses (including the previously reported case) had one or two supernumerary digits on their forelimbs and one additional case was diagnosed using radiography. Additional digits were located on the medial side of the forelimbs in all nine polydactyl horses. Radiography highlighted variable expression of the defect, which was either unilateral or bilateral. Variations were observed in the number of supernumerary phalanges, the level of development of a rudimentary metacarpal bone, the individualisation of a supernumerary digit and the existence of a rudimentary hoof. All nine affected horses were related to a single stallion. Pedigree analysis revealed that the most likely inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. A more complex mode could not be ruled out. Restricted recruitment of the family members due to confidentiality constraints and to international dispersal of the relatives, quality of radiographs. We describe an equine preaxial polydactyly in a Berber and Arabian-Berber family most likely with autosomal dominant inheritance with incomplete penetrance. This is the first description of an inherited non-syndromic polydactyly in horses. Des doigts surnuméraires, ou polydactylie, ont été décrit chez plusieurs espèces incluant l'homme, de même que les animaux domestiques et sauvages. Chez le cheval, il s'agit de la malformation congénitale des membres la plus fréquente, ayant été décrite dans des cas isolés seulement ou au sein de familles nucléaires. Une étiologie moléculaire n'a pas encore été rapportée. Caractériser le phénotype d'une polydactylie non syndromique de type préaxial au sein d'une famille équine et identifier un mode de transmission. TYPE D'ÉTUDE: Étude rétrospective. MÉTHODES: À partir d'un étalon Barbe polydactyle présenté à l'École Vétérinaire d'Alfort (France), 43 chevaux (8 polydactyles, 35 non‐polydactyles) de sa famille ont été recruté. Des examens cliniques, radiographiques et karyotypiques de certains chevaux de cette famille ont été faits. RÉSULTATS: Une famille équine Barde et Arabe croisé Barbe avec polydactylie préaxiale non syndromique a été identifiée. À l'examen clinique, huit chevaux ont montré un ou deux doigts surnuméraires au niveau des membres thoraciques et une jument a été diagnostiquée par radiographie. Les doigts additionnels étaient localisés du côté médial des membres thoraciques chez les 9 chevaux polydactyles. L'analyse radiographique a identifié une expression variable de ce défaut, soit unilatéral ou bilatéral. Des variations ont été observées quant au nombre de phalanges surnuméraires, pour le développement des os métacarpiens, pour l'individualisation d'un doigt surnuméraires et l'existence d'un sabot rudimentaire. L'ensemble des neuf chevaux étaient reliés au même étalon. L'analyse généalogique a révélé que le mode de transmission le plus probable était autosomique dominant avec une pénétrance incomplète et une expressivité variable. Une mode de transmission plus complexe ne peut être exclu. Recrutement restreint des membres de la famille due à des contraintes de confidentialité et des membres de la famille situés dans d'autres pays; qualité des radiographies. Nous avons découvert une polydactylie équine préaxiale chez une famille Barbe et Arabe croisé Barbe ayant le plus probablement un mode de transmission autosomique dominant avec pénétrance incomplète. À ce que nous sachions, ceci représente la toute première description de polydactylie non syndromique héréditaire chez le cheval.

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.

Preaxial polydactyly (PPD) is a congenital limb malformation, previously reported to be caused primarily by variants in the ZRS and upstream preZRS regions. This study investigated genetic variations associated with PPD, focusing on point variants and copy number variations (CNVs) in the ZRS and preZRS regions. Comprehensive genetic analyses were conducted on 102 patients with PPD, including detailed clinical examinations and Sanger sequencing of the ZRS and preZRS regions. Additionally, real-time quantitative PCR (qPCR) was used to detect CNVs in the ZRS region. The evolutionary conservation and population frequencies of identified variants were also evaluated. Six point variants were identified, among which four are likely pathogenic novel variants: 93G > T (g.156584477G > T), 106G > A (g.156584464G > A), 278G > A (g.156584292G > A), and 409A > C (g.156585378A > C). Additionally, qPCR analysis revealed that 66.67% of patients exhibited ZRS duplications. Notably, these duplications were also present in cases with newly identified potential pathogenic point variants. These findings suggest the possible interaction of point variants in ZRS and preZRS through a common pathogenic mechanism, leading jointly to PPD. The findings expand the variant spectrum associated with non-syndromic polydactyly and highlight that, despite different classifications, anterior polydactyly caused by variants in ZRS and nearby regions may share common pathogenic mechanisms. The incorporation of various variant types in genetic screening can effectively enhance the rate of pathogenic variant detection and contribute to the cost-effectiveness of genetic testing for limb developmental defects, thereby promoting healthy births.

This case report examines a newborn with bilateral postaxial polydactyly type B, delivered by a 42-year-old mother with a history of third-degree consanguinity. The mother, having had no prior live births and one abortion, presented at 39 weeks gestation. The absence of prenatal care is noted, with its potential impact on prenatal diagnosis not assessed. The newborn, a healthy girl, weighed 3400 g with an Apgar score of 9/10. Radiographic and physical examination revealed vestigial sixth digits with rudimentary phalanges, influencing the surgical approach. This report underscores the importance of genetic counseling in cases of consanguinity and illustrates the multidisciplinary strategy necessary for managing polydactyly, from surgical considerations to genetic evaluation.

CREBBP has been extensively studied in syndromic diseases associated with skeletal dysplasia. However, there is limited research on the molecular mechanisms through which CREBBP may impact bone development. We identified a novel pathogenic CREBBP variant (c.C3862T/p.R1288W, which is orthologous to mouse c.3789 C > T/p.R1289W) in a patient with non-syndromic polydactyly. We created a homozygous Crebbp p.R1289W mouse model and compared their skeletal phenotypes to wild-type (WT) animals. Bone marrow stem cells (BMSCs) were isolated and assessed for their proliferative capacity, proportion of apoptotic cells in culture, and differentiation to chondrocytes and osteocytes. We observed a significant decrease in body length in 8-week-old homozygous Crebbp p.R1289W mice. The relative length of cartilage of the digits of Crebbp p.R1289W mice was significantly increased compared to WT mice. BMSCs derived from Crebbp p.R1289W mice had significantly decreased cell proliferation and an elevated rate of apoptosis. Consistently, cell proliferative capacity was decreased and the proportion of apoptotic cells was increased in the distal femoral growth plate of Crebbp p.R1289W compared to WT mice. Chemical induction of BMSCs indicated that Crebbp p.R1289W may promote chondrocyte differentiation. The Crebbp p.R1289W variant plays a pathogenic role in skeletal development in mice. CREBBP has been extensively studied in syndromic diseases characterized by skeletal dysplasia. There is limited research regarding the molecular mechanism through which CREBBP may affect bone development. To our knowledge, we generated the first animal model of a novel Crebbp variant, which is predicted to be pathogenic for skeletal diseases. Certain pathogenic variants, such as Crebbp p.R1289W, can independently lead to variant-specific non-syndromic skeletal dysplasia.