De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2–47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype–genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay.

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Lhcb and other nuclear genes for chloroplastic proteins are regulated by several signals. Among them, light and retrograde signals from the plastid itself appear to act through closely related mechanisms. To investigate this interaction, we analysed an Arabidopsis mutant, hy1, deficient in plastidic heme oxygenase. hy1 is defective in phytochrome chromophore biosynthesis, which has other indirect effects on tetrapyrrole metabolism. We generated double mutants between hy1-6.2, genetically a null mutation, and three known gun (genome uncoupled) mutants, defective in retrograde plastid signalling. Recent molecular evidence shows GUN5 to be involved in tetrapyrrole metabolism (N. Mochizuki and J. Chory, manuscript in preparation). We observed hy1gun4 to be semi-albino plants, and hy1gun5 albino lethal, in a high-light-sensitive manner. Both double mutants showed defective greening and chloroplast development, and expressed Lhcb at reduced levels specifically in high light. Their degree of 'genome uncoupling' (Lhcb expression in the absence of functional chloroplasts) was similar to that observed in single mutants. These results can be interpreted as a metabolic (rather than genetic) interaction between HY1 and GUN4 or GUN5, and this in turn supports the involvement of tetrapyrroles as plastid signals. The tetrapyrrole precursor 5-aminolevulinic acid (ALA) inhibited Lhcb expression in hy1. Surprisingly, ALA also rescued photomorphogenesis of hy1. We speculate that either one tetrapyrrole intermediate, which can accumulate anomalously in hy1, or an altered ratio between two intermediates, plays a role as a repressor of Lhcb expression. gun1 did not exacerbate the plastid or Lhcb expression phenotype of hy1. This can be interpreted as a role for gun1 strictly on the same pathway as hy1 or, more likely, as evidence for the existence of at least one separate, non-tetrapyrrole related plastid signal.

Objective To analyse the results of the first 2 years of a QF-PCR stand-alone testing strategy for the prenatal diagnosis of aneuploidy in the London region and to determine the advantages and disadvantages of this policy.Methods A review of the results of 9737 prenatal samples received for exclusion of chromosome abnormalities. All samples were subjected to QF-PCR testing for common aneuploidies but only samples fulfilling specific criteria subsequently had a full karyotype analysis. ResultsOf the 9737 samples received, 10.3% had a chromosome abnormality detected by QF-PCR testing. Of the 7284 samples received with no indication for karyotype analysis, 25 (0.3%) received a normal QF-PCR result but subsequently had an abnormal karyotype detected either prenatally as a privately funded test or postnatally. Of these samples, without subsequent abnormal ultrasound findings, five had a chromosome abnormality associated with a poor prognosis, representing 0.069% of samples referred for Down syndrome testing.Conclusion While back-up karyotyping is required for some samples, using QF-PCR as a stand-alone prenatal test for pregnancies without ultrasound abnormalities reduces costs, provides rapid delivery of results, and avoids ambiguous and uncertain karyotype results, reducing parental anxiety.