DNA methylation profiling and genomic analysis in 20 children with short stature who were born small-for-gestational age

PURPOSE: In a significant proportion of children born small-for-gestational age (SGA) with failure of catch-up growth, the etiology of short stature remains unclear after routine diagnostic work-up. We wanted to investigate if extensive analysis of the (epi)genome can unravel the cause of growth failure in a significant portion of these children.

PATIENTS AND METHODS: Twenty SGA children treated with growth hormone (GH) because of short stature were selected from the BELGROW database of the Belgian Society for Pediatric Endocrinology and Diabetology for exome sequencing, SNP array and genome-wide methylation analysis to identify the (epi)genetic cause. First year response to GH was compared to the response of SGA patients in the KIGS database.

RESULTS: We identified (likely) pathogenic variants in 4 children (from 3 families) using exome sequencing and found pathogenic CNV in 2 probands using SNP array. In a child harboring a NSD1-containing microduplication, we identified a DNA methylation signature that is opposite to the genome-wide DNA methylation signature of Sotos syndrome. Moreover, we observed multi-locus imprinting disturbances in two children in whom no other genomic alteration could be identified. Five out of 6 children with a genetic diagnosis had an "above average" response to GH.

CONCLUSIONS: The study indicates that a more advanced approach with deep genotyping can unravel unexpected (epi)genomic alterations in SGA children with persistent growth failure. Most SGA children with a genetic diagnosis had a good response to GH treatment.