Genome Arrays for the Detection of Copy Number Variations in Idiopathic Mental Retardation, Idiopathic Generalized Epilepsy and Neuropsychiatric Disorders: Lessons for Diagnostic Workflow and Research

Abstract

We review the contributions and limitations of genome-wide array-based identification of copy number variants (CNVs) in the clinical diagnostic evaluation of patients with mental retardation (MR) and other brain-related disorders. In unselected MR referrals a causative genomic gain or loss is detected in 14–18% of cases. Usually, such CNVs arise de novo, are not found in healthy subjects, and have a major impact on the phenotype by altering the dosage of multiple genes. This high diagnostic yield justifies array-based segmental aneuploidy screening as the initial genetic test in these patients. This also pertains to patients with autism (expected yield about 5–10% in nonsyndromic and 10–20% in syndromic patients) and schizophrenia (at least 5% yield). CNV studies in idiopathic generalized epilepsy, attention-deficit hyperactivity disorder, major depressive disorder and Tourette syndrome indicate that patients have, on average, a larger CNV burden as compared to controls. Collectively, the CNV studies suggest that a wide spectrum of disease-susceptibility variants exists, most of which are rare (<0.1%) and of variable and usually small effect. Notwithstanding, a rare CNV can have a major impact on the phenotype. Exome sequencing in MR and autism patients revealed de novo mutations in protein coding genes in 60 and 20% of cases, respectively. Therefore, it is likely that arrays will be supplanted by next-generation sequencing methods as the initial and perhaps ultimate diagnostic tool in patients with brain-related disorders, revealing both CNVs and mutations in a single test.

A genetic model for neurodevelopmental disease

“…Intermediate burdens were observed for idiopathic generealized epilepsy (IGE), autism spectrum disorder (ASD) and schizophrenia. While CNV studies for children with ID/DD show an increase of 14.2% for large CNVs, the burden is lower for ASD [1, 21,22] with a diagnostic yield around 6-8% predominantly from de novo CNVs [18,21,22]. Studies of adults with schizophrenia and epilepsy demonstrate lower diagnostic yields of ~5% [11,12,18,23,24].…”

“…While CNV studies for children with ID/DD show an increase of 14.2% for large CNVs, the burden is lower for ASD [1, 21,22] with a diagnostic yield around 6-8% predominantly from de novo CNVs [18,21,22]. Studies of adults with schizophrenia and epilepsy demonstrate lower diagnostic yields of ~5% [11,12,18,23,24]. For other neurodevelopmental conditions there is either conflicting evidence for increased CNV burden, such as for bipolar disorder [25,26], or no evidence, as for Tourette's syndrome and dyslexia [19,20,27].…”

“…For other neurodevelopmental conditions there is either conflicting evidence for increased CNV burden, such as for bipolar disorder [25,26], or no evidence, as for Tourette's syndrome and dyslexia [19,20,27]. In all cases burden statistics are more significant when considering de novo events exclusively [15,18,21,22,26].…”

“…CNV and early genome sequencing experiments both implicate hundreds to thousands of different genes underlying various neurological phenotypes [22,39]. Analyses of candidate genes, however, are beginning to converge on a subset of protein-protein interaction networks or biological processes, many of which are strongly tied to neurodevelopment [18,52,[62][63][64]. Genes involved in synaptic function have been repeatedly shown to play a role in neurological disorders [62,63,65,66].…”

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability

“…Molecular karyotyping is the most common technique used today in ID investigation, and gross chromosomal abnormalities explain up to 15% of the cases. 2 Despite this, more than 60% of patients have no identifiable genetic cause. 3 The recent introduction of next-generation sequencing technologies has opened new possibilities, making the detection of causal variants more economical and faster.…”