Exome Pool-Seq in neurodevelopmental disorders.

High throughput sequencing has greatly advanced disease gene identification, especially in heterogeneous entities. Despite falling costs this is still an expensive and laborious technique, particularly when studying large cohorts. To address this problem we applied Exome Pool-Seq as an economic and fast screening technology in neurodevelopmental disorders (NDDs). Sequencing of 96 individuals can be performed in eight pools of 12 samples on less than one Illumina sequencer lane. In a pilot study with 96 cases we identified 27 variants, likely or possibly affecting function. Twenty five of these were identified in 923 established NDD genes (based on SysID database, status November 2016) (ACTB, AHDC1, ANKRD11, ATP6V1B2, ATRX, CASK, CHD8, GNAS, IFIH1, KCNQ2, KMT2A, KRAS, MAOA, MED12, MED13L, RIT1, SETD5, SIN3A, TCF4, TRAPPC11, TUBA1A, WAC, ZBTB18, ZMYND11), two in 543 (SysID) candidate genes (ZNF292, BPTF), and additionally a de novo loss-of-function variant in LRRC7, not previously implicated in NDDs. Most of them were confirmed to be de novo, but we also identified X-linked or autosomal-dominantly or autosomal-recessively inherited variants. With a detection rate of 28%, Exome Pool-Seq achieves comparable results to individual exome analyses but reduces costs by >85%. Compared with other large scale approaches using Molecular Inversion Probes (MIP) or gene panels, it allows flexible re-analysis of data. Exome Pool-Seq is thus well suited for large-scale, cost-efficient and flexible screening in characterized but heterogeneous entities like NDDs.

Quantitative assessment of the association between XRCC6 C1310G polymorphism and cancer risk.

X-ray cross-complementing group 6 (XRCC6) plays an important role in the DNA double-strand breaks repair and the maintenance of genomic integrity. XRCC6 C1310G polymorphism may be involved in the development of cancer through increasing genomic damages. However, studies investigating the relationship between XRCC6 C1310G polymorphism and cancer risk yielded contradictory results. To shed some light on these inconsistent findings, a meta-analysis was performed to clarify the effect of XRCC6 C1310G polymorphism on the susceptibility of cancer. A systemic literature search of PubMed, EMBASE, and China National Knowledge Infrastructure databases was conducted from their inception to September 26, 2012. The association between XRCC6 C1310G and cancer risk was assessed by the pooled odds ratio (OR) with 95 % confidence intervals (95 % CI) calculated by meta-analysis. A total of 15 eligible studies (4,642 cancer cases and 6,059 controls) were identified. Overall, there was obvious evidence for an association between XRCC6 C1310G polymorphism and increased risk of cancer under two genetic comparisons (GG vs. CC: fixed-effect OR 1.35, 95 % CI 1.10-1.66, I (2) = 17.0 %; GG vs. CG/CC: fixed-effect OR 1.25, 95 % CI 1.02-1.53, I (2) = 0.0 %). Subgroup analysis indicated that the association was significant in Asians (G vs. C: random-effect OR 1.13, 95 % CI 1.01-1.26, I (2) = 51.3 %; GG vs. CC: fixed-effect OR 1.43, 95 % CI 1.14-1.81, I (2) = 0.0 %; GG vs. CG/CC: fixed-effect OR 1.37, 95 % CI 1.09-1.72, I (2) = 0.0 %), but not in Europeans. Data from the current meta-analysis support the existence of an association between XRCC6 C1310G polymorphism and cancer risk in Asians. Studies with larger sample size are needed to further evaluate the influence of XRCC6 C1310G polymorphism on susceptibility of various cancers.