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The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year. Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described. De novo mutations in developmental disorders Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging de novo mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic de novo mutations in coding sequences resulting in disrupted or altered protein function.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3 , identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language. Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Nuclear energy is a cleaner energy form that can reduce the consumption of fossil fuels and minimize the emission of carbon dioxide. The major cost is that the nuclear wastes generated in the fission process and spent fuel reprocessing must be properly treated and converted to stable waste forms for long-term storage in geological repositories. Due to their high mobility in the aqueous media of the earth’s critical zone, radioactive iodine (129I and 131I), particularly, in anionic forms (iodide, I–, and iodate, IO3–) causes negative environmental impacts and potentially leads to health issues. This thesis is on the separation and electrochemical sensing of anionic iodine species from aqueous media using nickel (Ni)-based layered double hydroxides (LDHs). LDHs are brucite-like layered materials with positively charged layers, open interlayer space, electrochemically sensitive and redox-active surfaces, and intercalated charge-balancing anions. Therefore, they have great potential for the separation and detection of I– and IO3–. Here, I document a set of systematic studies, including (i) the energetic, thermal, and structural stability of NiAl-LDH-CO32–, NiAl-LDH-I–, and NiAl-LDH-IO3–, (ii) the electrochemical sensing of I– and IO3– employing NiM-LDH-CO32– (M3+ = Al3+, Cr3+ and Fe3+). The results suggest that the formation of NiAl-LDH-I– is thermodynamically more favorable than NiAl-LDH-CO32– , more exothermic by ~30 kJ/mol LDH, while intercalation of IO3– results in significantly decreased energetic stability by ~100 kJ/mol LDH. On the other hand, when M3+ = Al3+ and Cr3+, the specific capacity are significantly modified by I– and IO3– exchange suggesting high sensitivity suitable for anionic iodine sensing. The magnitudes of specific capacities for NiFe-LDH-CO32– , NiFe-LDH-I- and NiFe-LDH-IO3– are low all below 1.0 mAh/g. Therefore, according to the data in this thesis NiFe-LDH-CO32– may not be sensitive enough to detect I– and IO3– . The fundamental calorimetric and electrochemical insights of this thesis may benefit iodine waste form design and anionic iodine sensing.

\"Beautiful and brainy\" would be a perfect description of LaReine LaMar -- except that she's also a performer, a songwriter, an athlete and energetic enough for a whole group of girls.

Fresh lemon will add a tangy taste to some favorite recipes as the days become cold. You can welcome the family home to three mouth-watering Savory Lemon...

Entertaining now moves indoors or to the covered patios and porches. It is also the time of year when cool breezes whet appetites for something especially refreshing.

Simmer honey, wine, bottled lemon juice, cloves and cinnamon. Add fruit and simmer 15 minutes or until tender. Pack into hot jars. Pour hot syrup over fruit; seal. Yield: two pints. Combine sugar, water and bottled lemon juice in large saucepan. Tie spices loosly in cheesecloth; add to sugar and water. Boil 10 minutes. Add cleaned fruit, a few at a time, and cook until tender. Pack hot into hot jars; cover with hot syrup and seal. Makes four pints. NOTE: Pickled Fruits or Fruit in Wine and Honey may be served as a meat accompaniment.

What is the most disliked household task? Ironing, according to a recent survey. While automatic washers and dryers have relieved women of much washday drudgery, ironing is still a chore which has not been automated.