The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature
Ledjona Toni, Lukáš Plachý, Petra Dušátková, Shenali Anne Amaratunga, Lenka Elblová, Zdenĕk Šumnı́k, Stanislava Kolouskova, Marta Šnajderová, Barbora Obermannová, Štěpánka Průhová, Jan Lebl
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.