Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified > 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Purpose To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia. Methods We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN and VLDLR) or by whole exome sequencing. 55 patients studied in another institution were added as a validation cohort. Results The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. 19% remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia or mild frontal pachygyria. Conclusions The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (v 2 TDT ¼4.93, 1 df, P¼0.026) and the putative 'high-activity' alleles of the MAO-A promoter VNTR polymorphism (v 2 TDT ¼7.124, 1 df P¼0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.

To the authors' dismay, a software bug adversely affected some but not all of the main conclusions of this article. They reported that redundant biochemical networks provide greater genetic buffering than do gene families, on the basis of the rate of gene evolution for genes in the glycolysis/gluconeogenesis and the folate/homocysteine pathways. A bug in software that converted ClustalW alignments into Mega2.1 format considerably affected the data set for these two pathways, which contributed to the second mode of the Ka/Ks distribution (faster evolving genes). This bug did not affect results for other pathways, because those data were analyzed with a different and, unbeknownst to the authors, corrected version of the software. Reanalysis of the entire data set with the corrected software shows that redundant networks do not contribute more to genetic buffering than do gene families. One of the main conclusions from the data should now be that redundant networks provide no greater genetic buffering than do gene families. The fifth line of the abstract should now read "We found that genes with redundant networks evolve at similar rates as did genes without redundant networks." In addition, the glycolysis and gluconeogenesis pathways do not show distinct patterns of variation (average Ka/Ks = 0.108) compared with other pathways. The authors regret this error.

Background : Most cases of breast and ovarian cancer susceptibility remains unexplained. Testing multiple genes in one go with next generation sequencing is then an asset with the recent discovery of new genes involved in breast and ovarian cancer susceptibility. Methods : We studied 457 patients originated from Burgundy (France) fulfilling the criteria for BRCA1/2 testing using a next generation sequencing 25-gene panel including 17 genes of predisposition for breast and/or ovarian cancer (ATM, BARD1, BRCA 1/2, BRIP1, CHEK2, PALB2, RAD51C, TP53, PTEN, RAD50, MRE11, MLH1, MSH2, MSH6, PMS2, STK11). Results : A pathogenic BRCA1/2 mutation was found in 8% (n=37) of patients. Besides, we found 39 deleterious or probably deleterious mutations in 13 different genes. The most frequently mutated genes were CHEK2 (n=10 ; 2.1 %), ATM (n=9 ; 2 %), and PALB2 (n=4 ; 0.9%). One patient had deleterious mutations in both TP53 and PALB2, and another one had deleterious mutations in both BRCA2 and CHEK2. The mutation could explain the phenotype in the majority of cases, but a pathogenic mutation was found in a different predisposing gene in 7 patients, and could be considered as incidental findings with the currently published spectrum of cancer locations. Conclusion : Besides BRCA1/2 mutations, that remain the most frequent susceptibility genes for breast and ovarian cancer, gene panels remain a powerful tool for identifying the other less frequent susceptibility genes. The penetrance and spectrum of cancer associated to these other genes remain sometimes undefined, and further collaborative work is crucially needed to address this question. The possibility of double hits should led to careful genetic counseling. Citation Format: Eliade M, Skrypski J, Baurand A, Jacquot C, Bertolone G, Loustalot C, Coutant C, Guy F, Fumoleau P, Rivière J-B, Duffourd Y, Ghiringhelli F, Végran F, Boidot R, Lizard S, Faivre L. The power of next generation sequencing in the detection of breast and ovarian cancer susceptibility genes other than BRCA. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-04.