BackgroundThe recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.ObjectiveTo define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.MethodsWe collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.ResultsWhen compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.ConclusionsThe 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families, and homozygous loss of function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

Background New intraparenchymal brain injury on MRI is observed in 36–73% of neonates after cardiac surgery with cardiopulmonary bypass (CPB). Brain immaturity in this population is common. We performed brain magnetic resonance imaging (MRI) before and after neonatal cardiac surgery, using a high flow CPB protocol, hypothesizing that MRI brain injury would be associated with brain immaturity. Methods CPB protocol included 150 ml/kg/min flows, pH stat management, hematocrit >30%, and high flow antegrade cerebral perfusion. Regional brain oxygen saturation (rSO2) was monitored, with a treatment protocol for rSO2 <50%. Brain MRI, consisting of T1, T2, and diffusion weighted imaging, and MR spectroscopy were performed preoperatively, 7 days postoperatively, and at age 3–6 months. Results Twenty-four of 67 patients (36%) had new postoperative white matter injury (WMI), infarction, or hemorrhage, and 16% had new WMI. Associations with preoperative brain injury included low brain maturity score (p=0.002). Postoperative WMI was associated with single ventricle (SV) diagnosis (p=0.02), preoperative WMI (p<0.001) and low brain maturity score (p=0.05). Low brain maturity score was also associated with more severe postoperative brain injury (p=0.01). Forty-five patients had a 3rd scan, with a 27% incidence of new minor lesions, but 58% of previous lesions had partially or completely resolved. Conclusions We observed a significant incidence of both pre- and postoperative MRI abnormality, and an association with brain immaturity. Many lesions resolved in the first 6 months after surgery. Timing of delivery and surgery with bypass could affect the risk of brain injury.

Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3ε) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a ‘reverse genomics’ approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.