P352: Genetic diversity in breast cancer: Unveiling racial differences in mutation profiles

hedgehog (SHH) signaling pathway.Many congenital disorders caused by variations within the Hedgehog signaling pathway.GLI3 gene loss and gain variants are associated with the preaxial, postaxial synpolydactyly in Pallister Hall syndrome (PHS), and Greig cephalo-poly-syndactyly syndrome (GCPS), also nonsyndromic polydactyly.This represents the variability in GLI3 functions, but it is still unclear how far the quantity of GLI3 contributes to the development of normal limb buds.In this study, we focused on the patients associated with the rare congenital limb abnormalities of syndactyly, polydactyly, and nail dysplasia.Methods: A total of 43 outpatients of skeletal malformations from non-consanguineous families were enrolled in this study.We correlate the phenotype and genotype of the non-Apert polysyndactyly patients of different families.We performed exome sequencing, and further validation of SNV was performed by the Sanger sequencing.Trios exome sequencing was performed in selected families for CNV detection.RNA transcriptomic approach applied in selected patients for a deep understanding of the phenotype.Ethical clearance was taken from the Institute ethics committee and informed consent for enrolment of children was taken from the parents.Results: In patients with digital malformations, three familial cases were identified with a total of 7 affected patients with syndactyly, polydactyly, and nail hypoplasia/dysplasia. Family 1 (F1) (mother; daughter; son) patients presented with syndactyly in hands, feet, and polysyndactyly.Family 2 (F2) 1-year-old girl presented with a Y-shaped metacarpal, syndactyly in hands and polysyndactyly in feet and developmental delay.Family 3 (F3) (mother and two sons) presented with nail dysplasia, trident hands, oligodactyly, and polysyndactyly in feet in different individuals and developmental delay.Single nucleotide variant (SNV) was detected in 70% of patients and copy number variant (CNV) deletion in 30% of patients.Heterozygous missense SNVs were identified in the GLI3: c.3811G>C, p. A1271P in F1, GLI3: c.2110C>T,p.Gln704Ter in F2 and one CNV deletion in GLI3: c. (1497+1_1498-1)_(2103+1_2104-1)del (Exon 11-13 del) in F3.The phenotypic presentation in F3 was that of Wahaab syndrome.We also performed validation to segregate the other family members by Sanger sequencing for the SNV.RNA sequencing (patient-derived cells) in selected 4 patients with nail dysplasia, oligodactyly, and polydactyly in feet revealed higher expression of the ALPL, RUNX3, WNT4, COL1A9, and PTCH2 genes compared to controls.Conclusion: We identified Likely pathogenic SNV and CNV in GLI3 in syndactyly and polydactyly patients, broadening the genetic spectrum of GLI3 in families with dominant inheritance and contributed to better genetic counseling.A CNV was detected in a family with craniofacial symptoms, and syndactyly in the feet This study provides further evidence that the GLI3 transcription factor is the main cause in many cases of syn -polydactyly.Thus, GLI3 zinc-finger transcription factor plays an important role in human limb development and can present with variable phenotypes.GLI3 is a candidate transcription factor for molecular diagnosis in polysyndactyly.Further ex-vivo studies would enable understanding of GLI3 interactions with ALPL, RUNX3 and PTCH2.