The LMSz method - an automatable scalable approach to constructing gene-specific growth charts in rare disorders.

IntroductionChildren with monogenic neurodevelopmental disorders often grow abnormally. Gene-specific growth charts would be useful but require large samples to construct them using the conventional LMS method. MethodsWe transformed anthropometry to British 1990 reference z-scores for 328 UK and 264 international probands with ANKRD11, ARID1B, ASXL3, DDX3X, KMT2A or SATB2-related disorders, and modelled mean and standard deviation (SD) of the z-scores as gene-specific linear age trends adjusted for sex. Back-transforming the mean {+/-}2 SD lines provided gene-specific median, 2nd and 98th centiles. ResultsThe resulting z-score charts look plausible on several counts. Only KMT2A shows a (rising) age trend in median height, while BMI and weight increase in several genes, possibly reflecting population trends. Apart from SATB2 and DDX3X, the gene-specific medians are all below the reference (range 0.1th centile for height KMT2A to 36th centile for BMI ANKRD11). Median OFC shows no age trend, with medians ranging from 10th-30th centile, and ASXL3 lowest, on the 3rd centile. There are no sex differences in 19/24 cases. ConclusionsOur LMSz method produces gene-specific growth charts for rare diseases, an essential clinical tool for paediatric care. We plan to automate it within the DECIPHER platform, enabling availability for all relevant genes.