Identification of a novel ALMS1 pathogenic variant in a family with Cone-Rod Dystrophy using whole exome sequencing, followed by prenatal diagnosis

Abstract Purpose Cone-Rod Dystrophies (CRDs) are pigmentary retinopathies predominantly involving the macular cone photoreceptors leading to visual loss at an early age. Mutation analysis, especially in syndromic forms helps with diagnosis and disease management as well as prevention using preimplantation or prenatal diagnosis. However, it is hampered by genetic heterogeneity of CRDs. Here we report on successful application of whole exome sequencing (WES) in a family with autosomal recessive CRD, leading to prenatal diagnosis of Alstrom syndrome. Methods WES followed by data analysis focused on 316 genes associated with eye disorders, was carried out in the proband. Prenatal diagnosis of the detected pathogenic variant was then performed in the next pregnancy of the family. Results A novel homozygous pathogenic variant ( chr2: 73452376_73452377 delTC ) in exon 8 of the ALMS1 gene was identified which was confirmed by Sanger sequencing. The detected frameshift variant leads to loss of function of the ALMS1 protein, resulting in Alstrom syndrome phenotype. Prenatal diagnosis in the next pregnancy revealed that the fetus was carrier of the detected pathogenic variant. Conclusions This study provides further evidence that how recently developed high throughput sequencing can overcome the diagnostic hurdles encountered in heterogeneous disorders. It also demonstrates that this approach provides clinicians with new tools for early diagnosis, management, and prevention of such otherwise clinically hard-to-detect disorders. Hence, the “genotype-first” approach presented here is more likely to uncover the diagnosis of heterogeneous disorders compared to traditionally “phenotype-first” attitude.