Phelan‐McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2‐q13.33 terminal deletion detected in our sample of 63 PMS patients by array‐CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co‐dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype–phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence‐based genetic work‐ups, clinical assessments, and therapeutic interventions.

Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with monoallelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions. K E Y W O R D S autism spectrum disorder, compound heterozygosity, developmental delay, neurexin 1, Pitt-Hopkins-like syndrome 2, schizophrenia

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorder with a worldwide prevalence of about 5%. The disorder is characterized by inattentive, hyperactive and impulsive behavior and is often comorbid with other neuropsychiatric conditions. Array comparative genomic hybridization (array‐CGH) testing has been proved to be useful to detect chromosomal aberrations in several neuropsychiatric conditions including autism spectrum disorders (ASD) and intellectual disability (ID). The usefulness of array‐CGH in the ADHD clinics is still debated and no conclusive evidence has been reached to date. We performed array‐CGH in 98 children and adolescents divided in two similarly sized groups according to the clinical diagnosis: (a) one group diagnosed with ADHD as primary diagnosis; (b) the other group in which ADHD was co‐morbid with ASD and/or ID. We detected pathogenetic and likely pathogenetic copy number variants (CNVs) in 12% subjects in which ADHD was co‐morbid with autism and/or intellectual disability and in 8.5% subjects diagnosed with ADHD as primary diagnosis. Detection of CNVs of unknown clinical significance was similar in the two groups being 27% and 32%, respectively. Benign and likely benign CNVs accounted for 61% and 59.5% in the first and second group, respectively. Differences in the diagnostic yield were not statistically significant between the two groups (P > .05). Our data strongly suggest that array‐CGH (a) is a valuable diagnostic tool to detect clinically significant CNVs in individuals with ADHD even in the absence of comorbidity with ASD and/or ID and (b) should be implemented routinely in the ADHD clinics.

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The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal‐to‐intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family‐based and case–control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of “long” CAG alleles (≥17 repeats) to autistic children and of “short” alleles (≤16 repeats) to their unaffected siblings (all p < 10−5) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non‐HD controls have significantly lower frequencies of “short” CAG alleles compared to 185 unaffected siblings and higher rates of “long” alleles compared to 548 ASD patients from the same families (p < .05–.001). The SCA3 CAG repeat displays no association. “Short” HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while “long” alleles may enhance autism risk. Differential penetrance of autism‐inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic underpinnings. Microarray‐based comparative genomic hybridization (aCGH) technology has been proposed as a first‐level test in the genetic diagnosis of ASD and of neurodevelopmental disorders in general. Methods We performed aCGH on 98 Tunisian children (83 boys and 15 girls) diagnosed with ASD according to DSM‐IV criteria. Results “Pathogenic” or “likely pathogenic” copy number variants (CNVs) were detected in 11 (11.2%) patients, CNVs of “uncertain clinical significance” in 26 (26.5%), “likely benign” or “benign” CNVs were found in 37 (37.8%) and 24 (24.5%) patients, respectively. Gene set enrichment analysis involving genes spanning rare “pathogenic,” “likely pathogenic,” or “uncertain clinical significance” CNVs, as well as SFARI database “autism genes” in common CNVs, detected eight neuronal Gene Ontology classes among the top 10 most significant, including synapse, neuron differentiation, synaptic signaling, neurogenesis, and others. Similar results were obtained performing g: Profiler analysis. Neither transcriptional regulation nor immune pathways reached significance. Conclusions aCGH confirms its sizable diagnostic yield in a novel sample of autistic children from North Africa. Recruitment of additional families is under way, to verify whether genetic contributions to ASD in the Tunisian population, differently from other ethnic groups, may involve primarily neuronal genes, more than transcriptional regulation and immune‐related pathways.

We describe a 32-year-old male patient diagnosed with high-functioning autism spectrum disorder carrying a de novo 196-kb interstitial deletion at chromosome 17q11.2. The deletion was detected by array CGH (180K Agilent) and confirmed by quantitative PCR on genomic DNA. The deleted region spans the entire PSMD11 and CDK5R1 genes and partially the MYO1D gene. The CDK5R1 gene encodes for a regulatory subunit of the cyclin-dependent kinase 5 responsible for its brain-specific activation. This gene has been previously associated with intellectual disability in humans. A reduction in CDK5R1 transcript was detected, consistent with the genomic deletion. Based on the functional role of CDK5R1, this gene appears as the best candidate to explain the clinical phenotype of our patient, whose neuropsychological profile has more resemblance with some of the higher brain function anomalies recently described in the CreER-p35 conditional knockout mouse model than previously described patients with intellectual disability.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with onset in early childhood, still diagnosed only through clinical observation due to the lack of laboratory biomarkers. Early detection strategies would be especially useful in screening high-risk newborn siblings of children already diagnosed with ASD. We performed RNA sequencing on peripheral blood, comparing 27 pairs of ASD children vs their sex- and age-matched unaffected siblings. Differential gene expression profiling, performed applying an unpaired model found two immune genes, EGR1 and IGKV3D-15, significantly upregulated in ASD patients (both p adj = 0.037). Weighted gene correlation network analysis identified 18 co-expressed modules. One of these modules was downregulated among autistic individuals (p = 0.035) and a ROC curve using its eigengene values yielded an AUC of 0.62. Genes in this module are primarily involved in transcriptional control and its hub gene, RACK1, encodes for a signaling protein critical for neurodevelopment and innate immunity, whose expression is influenced by various hormones and known "endocrine disruptors". These results indicate that transcriptomic biomarkers can contribute to the sensitivity of an intra-familial multimarker panel for ASD and provide further evidence that neurodevelopment, innate immunity and transcriptional regulation are key to ASD pathogenesis.