Phenotypic specificity in patients with neurodevelopmental delay does not correlate with diagnostic yield of trio-exome sequencing

Nadja Baalmann, Malte Spielmann, Gabriele Gillessen- Kaesbach, Britta Hanker, Julia Schmidt, Christina M. Lill, Yorck Hellenbroich, Bianca Greiten, Katja Lohmann, Joanne Trinh, Irina Hüning*

*Corresponding author for this work


In this study, we aimed to examine the diagnostic yield achieved by applying a trio approach in exome sequencing (ES) and the interdependency between the clinical specificity in families with neurodevelopmental delay. Thirty-seven families were recruited and trio-ES as well as three criteria for estimating the clinical phenotypic specificity were suggested and applied to the underaged children. All our patients showed neurodevelopmental delay and most of them a large spectrum of congenital anomalies. Applying the pathogenicity guidelines of the American College of Medical Genetics (ACMG), likely pathogenic (29.7%) and pathogenic variants (8.1%) were found in 40,5% of our index patients. Additionally, we found four variants of uncertain significance (VUS; according to ACMG) and two genes of interest (GOI; going beyond ACMG classification) (GLRA4, NRXN2). Spastic Paraplegia 4 (SPG4) caused by a formerly known SPAST variant was diagnosed in a patient with a complex phenotype, in whom a second genetic disorder may be present. A potential pathogenic variant linked to severe intellectual disability in GLRA4 requires further investigation. No interdependency between the diagnostic yield and the clinical specificity of the phenotypes could be observed. In consequence, trio-ES should be used early in the diagnostic process, independently from the specificity of the patient.

Original languageEnglish
Article number104774
JournalEuropean Journal of Medical Genetics
Issue number7
Pages (from-to)104774
Publication statusPublished - 07.2023

Research Areas and Centers

  • Research Area: Medical Genetics

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