The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature

Abstract

<b><i>Introduction:</i></b> Among children born small for gestational age, 10–15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. <b><i>Methods:</i></b> Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight &lt;−2 SD for gestational age and life-minimum height &lt;−2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. <b><i>Results:</i></b> The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (<i>LHX4</i>, <i>OTX2</i>, <i>PROKR2</i>, <i>PTCH1</i>, <i>POU1F1</i>), the GH-IGF-1 or IGF-2 axis (<i>GHSR</i>, <i>IGFALS</i>, <i>IGF1R</i>, <i>STAT3</i>, <i>HMGA2</i>), 2/74 (3%) the thyroid axis (<i>TRHR</i>, <i>THRA</i>), 17/74 (23%) the cartilaginous matrix (<i>ACAN</i>, various collagens, <i>FLNB</i>, <i>MATN3</i>), and 7/74 (9%) the paracrine chondrocyte regulation (<i>FGFR3</i>, <i>FGFR2</i>, <i>NPR2</i>)<i>.</i> In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (<i>CDC42</i>, <i>KMT2D</i>, <i>LMNA</i>, <i>NSD1</i>, <i>PTPN11</i>, <i>SRCAP</i>, <i>SON</i>, <i>SOS1</i>, <i>SOX9</i>, <i>TLK2</i>). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. <b><i>Conclusions:</i></b> The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.