Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

Abstract

Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

“…Analyzing the 4 selected studies on short stature as well as the present study, 7 recurrent CNVs and 1 uniparental disomy were identified in patients with short stature of unknown cause. These CNVs were characterized as large, de novo, and individually rare, similar to those from other conditions in which there might be genetic “hotspots” for chromosomal imbalances [19, 20]. These loci corresponded to 40.2% of the total pathogenic or probably pathogenic CNVs described in all studies in which the short stature phenotype was the main emphasized phenotype.…”

“…Recently, studies have recognized recurrent pathogenic or probably pathogenic CNVs associated with neurodevelopment disorders, ovarian cancer, and heart diseases, indicating that there might be some genetic “hotspots” predisposing to different diseases [19-21]. Analyzing the 4 selected studies on short stature as well as the present study, 7 recurrent CNVs and 1 uniparental disomy were identified in patients with short stature of unknown cause.…”

Systematic identification of lincRNA‐based prognostic biomarkers by integrating lincRNA expression and copy number variation in lung adenocarcinoma

“…Next, we screened for the lincRNAs that showed expression changes due to copy number alterations ( p < 0.05 according to t ‐test). CNVs are considered as risk factors for cancer, as these large‐sized genomic alterations may encompass key genes that contribute to carcinogenesis and disease progression . These copy number altered lincRNAs were termed as risk lincRNAs.…”

Genomics for paediatricians: promises and pitfalls

“…However, if significant in terms of either the number and/or functional significance of the genes involved, they can be associated with a clinical phenotype. Some of these CNVs are recurrent and are now being categorised as syndromes 3. However, as with most genetic conditions, there is often variable expression or reduced penetrance 4…”