Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Multiplex Consanguineous Family Highlights CLASP1 as a Candidate Gene for Lissencephaly.

Background and Objectives: Noncentrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CLASP family of molecules. To date, no human monogenic disorder has been associated with the CLASP1 gene. In this study, we aimed to delineate the clinical and neuroradiologic phenotype associated with biallelic CLASP1 variants. Methods: We analyzed clinical characteristics, MRI data, and genotypes of a cohort of 3 patients with homozygous variants in CLASP1. Results: Homozygous CLASP1 variant is associated with primary microcephaly, severe neurodevelopmental delay, and early-onset refractory epilepsy. The neuroradiologic phenotype comprises a highly recognizable combination of classic lissencephaly, with the posterior gradient more severe than the anterior gradient, a thin/hypoplastic splenium of the corpus callosum, mild enlargement of the lateral ventricles primarily posteriorly with a squared pattern, and pontine hypoplasia. Discussion: This study underscores the role of CLASP1 in brain development and suggests that the identified variant disrupts CLASP1 interaction with the microtubule cytoskeleton, contributing to lissencephaly pathogenesis.

The Effect of Slime Factor in the Treatment of Spinal Implant Infections.

AIM: To investigate the effect of the biofilm-forming ability of the bacteria on treatment in rats by using biofilm-forming and nonbiofilm- forming strains of Staphylococcus aureus (S. aureus). MATERIAL AND METHODS: Forty rats were divided into four equal groups as Group 1A, 1B, 2A, and 2B. All rats underwent single distance lumbar laminectomy, and titanium implants were introduced. Group 1 rats were inoculated with Slime factor (-) S. aureus, while Group 2 rats were inoculated with biofilm Slime factor (+) S. aureus. None of the rats were given antibiotics. One week later, the surgical field was reopened and microbiological samples were taken. The implants of rats in Groups 1A and 2A were left in place, while the implants of rats in Groups 1B and 2B were removed. RESULTS: There was no statistically significant difference between the groups inoculated with slime factor (+) S. aureus; although, Groups 1A and 2A showed statistically significant difference. Statistical analysis with respect to bacterial count also showed a statistically significant difference between Groups 1A and 2A. There was a statistically significant difference between Group 1B and 2B. CONCLUSION: The results obtained in the present study reveal that in case of implant-dependent infection, the first sample taken can be checked for slime factor, and if there is infection with slime factor-negative bacterium, treatment without removing the implant may be recommended. S. aureus was used in the study because it is the most common cause of implant-related infection at surgical sites. Further studies using different bacterial species are needed to reach a definitive conclusion.