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OP-121 Diagnostic yield of WES in pediatric patients: a single-center experience
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  1. Çağrı Oğur,
  2. Büşra Kaya,
  3. Berna Ayar,
  4. Hüseyin Avni Taç,
  5. Narmin Bakhshaliyeva,
  6. Hakan Berkil
  1. GENETİKS Global Genetic Disorders Evaluation Center and Laboratories

Abstract

Aim This study aims to assess the diagnostic yield of Whole Exome Sequencing (WES) in pediatric patients presenting with diverse clinical indications within a specialized genetic evaluation center.

Material and Method WES was conducted on 741 pediatric patients, presenting with neurological, metabolic, musculoskeletal, cardiovascular, sensory, autoimmune, and complex conditions. Approximately 20% of patients originated from consanguineous families. Exonic regions were sequenced at an average coverage of 100X using the Novaseq 6000 next-generation sequencing platform. Bioinformatic analysis followed the manufacturer’s recommended workflow, and variant analysis adhered to ACMG criteria, ClinVar, and HGMD. Sanger sequencing with region-specific primers was employed for segregation analysis.

Results WES analysis identified reportable pathogenic variants and/or variants of uncertain significance (VUS) in 548 out of 741 patients with neurological (73.5%, n=511), metabolic (71.4%, n=42), musco-skelatal (78%, n=41), autoimmune (58.8%, n=34), skin (83.3%, n=6), cardiovascular (72.7%, n=11), sensory (100%, n=7) and multiple conditions (77.7%, n=63). Segregation analysis in 235 families confirmed the diagnosis in 181 cases, resulting in an overall diagnostic yield of 24.4% (181/741). Notably, 29 families with confirmed diagnoses underwent in vitro fertilization (IVF) and preimplantation genetic testing for monogenic disorders (PGT-M), leading to the successful birth of healthy infants.

Conclusions Following the exclusion of patients with only Variants of Uncertain Significance (VUS) and the inclusion of segregation analysis, the overall diagnostic confirmation rate reached 24.2%. To further improve confirmations, an extension of segregation analyses to include previously untested families (n=313) is warranted. Nevertheless, an acceptable diagnostic yield achieved in this study is notably influenced by the substantial prevalence of consanguineous cases. These findings underscore the crucial role of WES in pediatric conditions, not only in identifying novel and/or actionable genes with therapeutic applications but also in employing additional technologies, such as IVF and PGT-M, to prevent rare genetic disorders in subsequent generations within affected families.

  • Preimplantation Genetic Testing for Monogenic Conditions (PGT-M)
  • Metabolic Disorders
  • Neurologic Disorders
  • Rare Genetic Conditions
  • Whole Exome Sequencing (WES)

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