Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified

Parameterized complexity of DPLL search procedures

We study the performance of DPLL algorithms on parameterized problems. In particular, we investigate how difficult it is to decide whether small solutions exist for satisfiability and other combinatorial problems. For this purpose we develop a Prover-Delayer game that models the running time of DPLL procedures and we establish an information-theoretic method to obtain lower bounds to the running time of parameterized DPLL procedures. We illustrate this technique by showing lower bounds to the parameterized pigeonhole principle and to the ordering principle. As our main application we study the DPLL procedure for the problem of deciding whether a graph has a small clique. We show that proving the absence of a k-clique requires n^Ω(k) steps for a nontrivial distribution of graphs close to the critical threshold. For the restricted case of tree-like Parameterized Resolution, this result answers a question asked by Beyersdorff et al. [2012] of understanding the Resolution complexity of this family of formulas

A characterization of tree-like resolution size

We explain an asymmetric Prover-Delayer game which precisely characterizes proof size in tree-like Resolution. This game was previously described in a parameterized complexity context to show lower bounds for parameterized formulas (Beyersdorff et al. (2013) [2]) and for the classical pigeonhole principle (Beyersdorff et al. (2010) [1]). The main point of this note is to show that the asymmetric game in fact characterizes tree-like Resolution proof size, i.e. in principle our proof method allows to always achieve the optimal lower bounds. This is in contrast with previous techniques described in the literature. We also provide a very intuitive information-theoretic interpretation of the game

Brief report: Peculiar evolution of autistic behaviors in two unrelated children with brachidactyly-mental retardation syndrome

Brachidactyly-Mental Retardation (BDMR) Syndrome (MIM 600430) is associated with terminal deletions at chromosome 2q37 and a limited number of studies also reported an association between 2q37 → qter deletion and autism. Herein we describe two cases of autism in unrelated children with BDMR Syndrome, showing physical, cognitive, behavioral, and disease natural history homologies, with a very prominent social impairment in the first 4 years of life. At follow-up evaluations, spanning a 5-years period, both children experienced a progressive reduction of the autistic symptoms, besides retaining compromised cognitive ability. This report supports the hypothesis that genes in the 2q37 region may contribute to the etiology of autism, leading, however, to a peculiar evolution of the disease, with symptoms severity decreasing over time