Endocrine Abstracts

Rare diseases affect more than 300 million people worldwide, often lead to chronic illness, disability, and premature death. The recent advancements in genetics through Next Generation Sequencing (NGS) have revolutionized research and diagnostics. NGS technologies allowed the identification of novel candidate disease-causing genes, significantly also in-depth modification of our understanding of genetic architecture of various rare endocrine diseases. However, despite these recent advancements, over 50% of cases typically remain unsolved. In these unsolved cases, periodical reanalysis has been proposed as a solution to enhance the diagnostic yield. Here, we report results from WES reanalysis of patients with endocrine pathological phenotype from Telethon Undiagnosed Disease Program (TUDP). Our study aimed to identify potential novel disease-causing genes by focusing on unsolved patients, whereas reanalysis of solved patients could reveal potential link of already known disease-causing genes in the endocrine disorders. TUDP cohort comprised of 4809 solved and 6278 unsolved patients. Initially, we selected 359 patients among the solved and 227 patients from unsolved ones, based on human phenotype ontology (HPO). Successively, we considered 39 solved and 26 unsolved patients which had the strongest endocrine phenotype for this pilot study. WES data reanalysis was performed employing bioinformatics in-house pipelines, whereas human genome version 19 (hg19) was used as the reference genome in all cases. For variant interpretation, established guidelines were used as VarSome germline classification. Moreover, we also interrogated variants and genetic disorders databases to validate the association of genes with the patient’s phenotype. Furthermore, results from each analysis were compared with the most recent literature studies. Preliminary results obtained from solved patients led us to detect a de novo AFF2 mutation (NM_002025:c.1444G>A; p.Gly482Arg in exon 10) in a patient diagnosed with cryptorchidism. Among the unsolved patients, a heterozygous compound PKD1 variant (NM_001009944.3 :c.12436G>A; p.Val4146Ile and c.3496G>A; p.Gly1166Ser, respectively in exon 45 and 15) was observed in a patient with clinical presentation of Hypophosphatemic Rickets. To better understand the putative involvement of PKD1 gene in endocrine disorders, we are searching for other patients carrying variants in the same gene interrogating MatchMaker Exchange platforms, which facilitates the matching of phenotype-genotype for candidate disease-causing genes connecting researchers and clinicians worldwide. Based on these results, we provide practical evidence to increase novel genetic diagnosis through WES reanalysis. Finally, this study emphasizes the power of reanalysis of WES data, particularly in a clinical context given the implications.