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BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

THE Michaelis–Menten1 equation relating initial velocity of a simple enzyme-catalysed reaction to initial substrate concentration is: where ν is the initial velocity of reaction, e is the initial enzyme concentration, s is the initial substrate concentration, k3 is the velocity constant of the breakdown of the enzyme-substrate compound into enzyme and product of the catalysed reaction and K is the substrate concentration at which ν is half-maximal.

IN the recent communication under this title, Bolodia and Young1 say that “… no satisfactorily reproducible effect of growth hormone in vitro on carbohydrate metabolism has been described”. No grounds are given for rejecting the comprehensive evidence of Ottaway and Bulbrook2 for effects on the glucose uptake of rat diaphragm which are practically identical with those now described by Bolodia and Young, nor for the evidence of Bronk and Fisher3 that very small concentrations of bovine growth hormone produce anti-insulin effects on the perfused rat heart. Bronk and Fisher showed that growth hormone reduced glucose uptake and permeability to galactose in the absence of insulin as well as in its presence. It follows that growth hormone produces an effect which offsets the action of insulin but is not acting as an anti-insulin.

THE demonstration by Payne, Sansom, Garner, Thomson and Miles1 that small resin particles can penetrate the wall of the alimentary tract of the calf is clear, but their claim that similar processes may be of nutritional significance is open to doubt.