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

Abstract

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 withANKRD11, ARID1B, ASXL3, DDX3X, KMT2AorSATB2-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, 2ndand 98thcentiles.ResultsThe resulting z-score charts look plausible on several counts. OnlyKMT2Ashows a (rising) age trend in median height, while BMI and weight increase in several genes, possibly reflecting population trends. Apart fromSATB2andDDX3X,the gene-specific medians are all below the reference (range 0.1thcentile for heightKMT2Ato 36thcentile for BMIANKRD11). Median OFC shows no age trend, with medians ranging from 10th-30thcentile, andASXL3lowest, on the 3rdcentile. 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.