Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability

Abstract

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID.

Comprehensive evaluation of the child with global developmental delays or intellectual disability

“…Furthermore, more comprehensive testing for specific diseases is typically justified once the results become available. 2,7,10,12,17)…”

“…Genetic etiologies, including chromosomal abnormalities (e.g., microdeletions, microduplications, and trisomies), have been proposed to account for approximately half of GDD/ID cases. 2,10) Copy number variations, genetic deletions and duplications, and encompassing insertions are important contributors to human genetic diversity and sources of associated genetic mutations. The enhanced sensitivity of microarray-based genomic copy number analysis enables the detection of submicroscopic deletions and duplications, resulting in a significantly higher diagnostic yield than that of karyotyping (15% versus 7.4%, respectively).…”

“…Some examples of such syndromes include Prader-Willi and Angelman syndromes (deletion of 15q11-q13), Smith-Magenis syndrome (deletion of 17p12), Williams-Beuren syndrome (deletion of 7q11.23), and deletions in the CHRNA7 and SH2B1 genes, among others. 2,7,10,12) Interpreting variants of uncertain significance identified by CMA can be challenging, particularly when identifying incidental findings, such as the deletion of cancer predisposition genes such as FLCN or BMPR1A, which can have significant ethical implications, especially when investigating GDD/ID. Therefore, it is recommended that the interpretation of abnormal results and variants of unknown significance in the CMA test and subsequent counseling of families be performed by a medical geneticist and certified genetic counselor in collaboration with the reference laboratory and platform used.…”

“…Although the exact cause is often unknown, genetic factors contribute to approximately half of all cases. 2,10) Genetic testing has become an essential component of the diagnostic evaluation. The early identification of warning signs and underlying causes, along with the implementation of appropriate management strategies, is crucial for predicting the patient's clinical course, enhancing their intellectual functioning and developmental skills, and providing accurate prognostic counseling.…”

Clinical exome sequencing reveals an important role for clinical diagnosis of intellectual disability with definition of seven novel variants

“…A specific diagnosis provides social support and information sharing for the family and the physician. 2 The diagnostic evaluation should include detailed patient history and physical examination, standard karyotyping, fragile X molecular analysis, neurological imaging, and/or array comparative genomic hybridization (aCGH) studies with subtelomeric fluorescent in situ hybridization (FISH). With the aCGH method, an increase of 10% in diagnostic rate in cases with intellectual disability has been reported.…”