TY - JOUR
T1 - Phenotypic specificity in patients with neurodevelopmental delay does not correlate with diagnostic yield of trio-exome sequencing
AU - Baalmann, Nadja
AU - Spielmann, Malte
AU - Gillessen- Kaesbach, Gabriele
AU - Hanker, Britta
AU - Schmidt, Julia
AU - Lill, Christina M.
AU - Hellenbroich, Yorck
AU - Greiten, Bianca
AU - Lohmann, Katja
AU - Trinh, Joanne
AU - Hüning, Irina
N1 - Publisher Copyright:
© 2023 Elsevier Masson SAS
Copyright © 2023 Elsevier Masson SAS. All rights reserved.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85156271294&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/6528c4b6-92df-3f5c-a23b-9f96a8c54f68/
U2 - 10.1016/j.ejmg.2023.104774
DO - 10.1016/j.ejmg.2023.104774
M3 - Journal articles
C2 - 37120078
AN - SCOPUS:85156271294
SN - 1769-7212
VL - 66
SP - 104774
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
IS - 7
M1 - 104774
ER -