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

<p><b><span>Purpose:</span></b> 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.</p> <p><b><span>Patients and Methods:</span></b><span> Twenty </span><span>SGA</span><span> 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 </span>for<span> 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.</span></p> <p><b><span>Results:</span></b><span> 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 <i>NSD1</i>-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.</span></p> <p><b><span>Conclusions: </span></b><span>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.</span></p>