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

Introduction Children 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. Methods We 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, 2 nd and 98 th centiles. Results The 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 0.1 th centile for height KMT2A to 36 th centile for BMI ANKRD11 ). Median OFC shows no age trend, with medians ranging from 10 th -30 th centile, and ASXL3 lowest, on the 3 rd centile. There are no sex differences in 19/24 cases. Conclusions Our 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.