Molecular Characterization of NRXN1 Deletions from 19,263 Clinical Microarray Cases Identifies Exons Important for Neurodevelopmental Disease Expression

PURPOSE: The purpose of the current study was to assess the penetrance of NRXN1 deletions. METHODS: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. RESULTS: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P \u3c 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3\u27 end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5\u27 NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). CONCLUSIONS: The results support the importance of exons near the 5\u27 end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61

De Novo and Rare Inherited Copy-Number Variations in the Hemiplegic Form of Cerebral Palsy

PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs

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Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure - Fig 4

<p>Brain volume Z scores and normed head circumference (HC) standard deviations are shown to positively correlate in both the control (A) and prenatal alcohol exposure (PAE) groups (B).</p

When only including the 14 PAE participants below the clinical cutoff for microcephaly (HC ≤ 3^rd percentile, A–column 1), it is notable that 10 (~70%) of the subjects have brain volumes below the 3^rd percentile.

<p>Similarly, ~80% of the subjects with HC ≤ 10^th percentile have brain volumes under the 10^th percentile (A–column 2). Conversely, among the PAE participants with total brain volume ≤ 3^rd (n = 14, B–column 1) or 10^th percentile (n = 22, B—column 2), 55–65% of subjects have HC in the ‘normal’ range from the 11^th-99th percentiles, suggesting a disconnect between small brain volumes and head circumference. Note that the category of ≤ 10^th percentile on the x-axis of A and B includes subjects who are ≤ 3^rd percentile (to match cutoffs used in various diagnostic guidelines), while colour divisions within each bar are non-overlapping.</p