Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability

Abstract

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population

“…Doing so will subsequently increase knowledge within the scientific community and accelerate diagnosis for other MMS patients. We also observed that missense mutations were abundant in our cohort (43.2%) as it has also been observed in a recent study on patients with neurodevelopmental disorders and multiple congenital anomalies (40.8%) [41]. Even though the frequencies of autosomal recessive disorders and missense variants detected in this study are higher or similar to other larger studies, a more reliable frequency can be achieved with the continuity of this study and subsequent increase of the study's sample size.…”

Intellectual Developmental Disabilities:

“… 10 Generating substantial amounts of information, WES can reliably detect singe gene variants throughout the exome. 10 – 14 Fifteen to forty percent of persons with IDD who have WES will have a detectable mutation and a molecular diagnosis or determination made.…”

Pitt-Hopkins Syndrome: Clinical and Molecular Findings of a 5-Year-Old Patient

“…Regarding the molecular technique used on our PTHS patient, we admit that MLPA represents a fast multiplex technique that is useful and cost-effective, likely being the most efficient method for the detection of partial gene deletions (and duplications), but it does not allow for the precise characterization of the molecular defect [22][23][24][25]. NGS and aCGH analysis have shown that the genetic and phenotypic heterogeneity of patients with intellectual disabilities is very high.…”