No abstract

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.

Assigning single clinical features to their disease-locus in large deletions: the example of chromosome 1q23-25 deletion syndrome.

Tourette syndrome (TS) is a neurodevelopmental disturbance with heterogeneous and not completely known etiology. Clinical and molecular appraisal of affected patients is mandatory for outcome amelioration. The current study aimed to understand the molecular bases underpinning TS in a vast cohort of pediatric patients with TS. Molecular analyses included array-CGH analyses. The primary goal was to define the neurobehavioral phenotype of patients with or without pathogenic copy number variations (CNVs). Moreover, we compared the CNVs with CNVs described in the literature in neuropsychiatric disorders, including TS, to describe an effective clinical and molecular characterization of patients for prognostic purposes and for correctly taking charge. Moreover, this study showed that rare deletions and duplications focusing attention on significant genes for neurodevelopment had a statistically higher occurrence in children with tics and additional comorbidities. In our cohort, we determined an incidence of potentially causative CNVs of about 12%, in line with other literature studies. Clearly, further studies are needed to delineate the genetic background of patients with tic disorders in a superior way to elucidate the complex genetic architecture of these disorders, to describe the outcome, and to identify new possible therapeutic targets.

Background PARK2 (PRKN; MIM*602544) encodes Parkin protein, an ubiquitin‐protein ligase required for proteasomal degradation and operating in the synaptic compartments. Copy number variations (CNVs) involving PARK2 have been associated with autism spectrum disorder (ASD). We report on a family with ASD (multiplex family) harbouring a microdeletion at chr. 6q26 causing PARK2 disruption. Methods CNV analyses were performed using CGH/SNP‐array platforms, and the detected microdeletion was confirmed by real‐time quantitative PCR. Standardized psychometric evaluation was used for neurobehavioral characterization. Results We found an intragenic ~157 kb microdeletion of the chromosomal region 6q26 causing PARK2 disruption in two male sibs with ASD and syndromic phenotype. They both had dysmorphic facial features with coarse faces, deeply set eyes with long horizontal palpebral fissures, long eyelashes and thick eyebrows, fleshy lips and mild skeletal problems. We found an intrafamilial clinical heterogeneity owing to different severity of the autism symptoms between the affected sibs: the younger one had minimally verbal autism and severe intellectual disability, whereas his older brother presented high‐functioning autism and preserved speech. Parental analysis and real‐time PCR using a PRKN fragment mapping within the deletion demonstrated that the deletion was inherited from their father having subthreshold features of ASD consisting with broad autism phenotype. Conclusions The study corroborates the hypothesis that PARK2 aberrations may be associated with ASD and highlights correlations between CNV affecting PARK2 and ASD in a multiplex family. We show remarkable intrafamilial variability in the severity of inherited ASD associated with PARK2 microdeletion.