Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS)

Abstract Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120.