Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.

Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.

Transient nonketotic hyperglycinemia and defective serotonin metabolism in a child with neonatal seizures.

Neonatal nonketotic hyperglycinemia is usually fatal or, less commonly, severely developmentally disabling, whereas transient nonketotic hyperglycinemia has usually been followed by normal development. We report a boy who had transient neonatal nonketotic hyperglycinemia but a coexistent disorder of serotonin metabolism manifested by initially low cerebrospinal fluid 5-hydroxyindoleacetic acid (which later normalized), low whole blood serotonin, and decreased platelet serotonin uptake. He survived the neonatal period but was neurodevelopmentally delayed and developed an autistic-like disorder. Later, his positron emission tomographic (PET) scans with alpha[(11)C] methyl-l-tryptophan revealed a pattern characteristic of autistic children. Although we know of no link between glycine and serotonin metabolism, and our patient had low, rather than high, central and peripheral serotonin, this case might represent a novel infantile disorder that affects both the glycine and serotonin neurotransmitter systems.

Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): international multicenter study.

The efficacy of oral inosiplex alone (group A) versus combined treatment of inosiplex (Isoprinosine) and intraventricular interferon-alpha2b (Intron A) (group B) in patients with subacute sclerosing panencephalitis (SSPE) was compared. One hundred and twenty-one patients who met the diagnostic criteria for subacute sclerosing panencephalitis and presented at stage 2 or less were randomized into group A or B. Data were analyzable on 67 patients who met the inclusion criteria and adhered to the protocol. The inosiplex dosage was 100 mg/kg/day to a maximum of 3 g/day, taken orally in three divided doses for 6 months. Interferon-alpha2b started with 100,000 U/m2 and escalated to 1,000,000 U/m2 over 5 inpatient days and then 1,000,000 U/m2 twice a week for 6 months. Neurologic status was rated by the Neurological Disability Index, Brief Assessment Examination, and stages. Kaplan-Meier survival rates were not statistically significant between group A and group B (log-rank test chi2 = .1374, P = .7109). In longitudinal morbidity analyses, regression results were fitted to three outcome measures: the Neurological Disability Index, the Brief Assessment Examination, and stage. Group medians of the estimated regression slopes were then compared using the Wilcoxon rank-sum test. There was no statistically significant difference between the two groups on any of these three measures. Morbidity comparisons of clinical classification of outcomes (improvement, stabilization, worsening after treatment stopped, deterioration) also showed no statistically significant difference between groups. There were no statistically significant differences between the two treatment groups on any efficacy measure. However, the observed rates of satisfactory outcome (stabilization, improvement) of 34% in group A and 35% in group B were higher than the spontaneous remission rates of 5 to 10% reported in the literature, suggesting that treatment was superior to no treatment.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.