Neuropsychiatric disease (NPD) clustering in families with Autism Spectrum Disorder (ASD): genetic, epigenetic and environmental issues

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, epilepsy, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and further clinical presentation. Both miRNA and lncRNA are functional RNA molecules that are transcribed from DNA but not translated into proteins, instead they act as powerful regulators of gene expression. While miRNA are small noncoding RNAs with 22-25 nucleotides in length that act at the post-transcriptional level of gene expression, the lncRNA are bigger molecules (>200 nucleotides in length) that are capped, spliced, and polyadenylated, similar to messenger RNA. Although few lncRNA were well characterized until date, there is a great evidence that they are implicated in several levels of gene expression (transcription/post-transcription/post-translation, organization of protein complexes, cell– cell signaling as well as recombination) as shown in figure 1.

The clinical significance of 15q11.2 BP1-BP2 duplications: - Where do we stand?

The 15q11.2-q13 region has been well characterized, being associated with a range of syndromatic copy number variants (CNVs), and comprises five established break points sites (BP1 to BP5). While the clinical effect for BP1-BP3, BP2-BP3 and BP4-BP5 CNVs is well established, the same cannot be said for BP1-BP2 CNVs. Recently the 15q11.2 BP1-BP2 deletion has been reviewed, emerging as a microdeletion syndrome with low penetrance and variable expressivity being the CNV frequently inherited from a healthy parent. This microdeletion is considered to be a risk factor for several neurodevelopment disorders. For the reciprocal duplication the picture has been less conclusive. Aiming for a better understanding of the clinical significance of this CNV, we collected patients with intellectual disability and/or other clinical features, referred for microarray testing, gathering clinical details for the ones with the duplication. Data was collected from two genetic laboratories. With a total of 1545 patients, we identified eleven carrying the duplication at 15q11.2 BP1-BP2. It was possible to assess inheritance in only four cases, all inherited from a healthy parent. All patients presented intellectual disability,and facial dysmorphism was the second most common feature observed. Microcephaly, autism, congenital abnormalities, dystonia and cataplexy where reported individually. The magnitude of the effect of 15q11.2 duplication remains elusive, and the outcome unclear, posing a major challenge to genetic counseling. Nevertheless, we expect the collection of more of these cases will establish this gain, as it happened with the reciprocal deletion, as a microduplication syndrome with low penetrance and variable expressivity.

A 1.77 Mb deletion in 3p26.3 encompassing CNTN6 and CNTN4 genes: case report

Chromosome microarray analysis is a powerful diagnostic tool and is being used as a first-line approach to detect chromosome imbalances associated with intellectual disability, dysmorphic features and congenital abnormalities. This test enables the identification of new copy number variants (CNVs) and their association with new microdeletion/microduplication syndromes in patients previously without diagnosis. We report the case of a 7 year-old female with moderate intellectual disability, severe speech delay and auto and hetero aggressivity with a previous 45,XX,der(13;14)mat karyotype performed at a younger age. Affymetrix CytoScan 750K chromosome microarray analysis was performed detecting a 1.77 Mb deletion at 3p26.3, encompassing 2 OMIM genes, CNTN6 and CNTN4. These genes play an important role in the formation, maintenance, and plasticity of functional neuronal networks. Deletions or mutations in CNTN4 gene have been implicated in intellectual disability and learning disabilities. Disruptions or deletions in the CNTN6 gene have been associated with development delay and other neurodevelopmental disorders. The haploinsufficiency of these genes has been suggested to participate to the typical clinical features of 3p deletion syndrome. Nevertheless inheritance from a healthy parent has been reported, suggesting incomplete penetrance and variable phenotype for this CNV. We compare our patient with other similar reported cases, adding additional value to the phenotype-genotype correlation of deletions in this region.