ESPE Abstracts

Introduction: Statural growth is regulated by multiple genetic, epigenetic and environmental mechanisms. The GH-IGF-1 axis was long believed to be the main linear growth regulator in children until more recent studies showed that the complex regulation of growth plate chondrocytes play an equal role. In order to extend our knowledge about the genes involved in short stature, we studied a unique cohort of children with short stature from consanguineous families living in Sulaymani in Kurdistan, Iraq.

Patients and Methods: Fifty-five consanguineous families, with children shorter than -2.3 SDS at the time of examination (median height -3.3SDS), who were examined at the pediatric endocrine outpatient clinic of the Dr. Jamal Pediatric Teaching Hospital in Sulaimani between January 2018 and February 2020, were included in the study. In families with more than one child with short stature, the shorter sibling was selected as the proband (median age 8 years). Four non-related patients were subsequently excluded due to the later diagnosis of Turner, Edwards and Silver-Russell syndromes. With their consent, the remaining 51 probands’ DNA was analyzed by Whole Exome Sequencing (WES) methods. The data were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Selected potentially pathogenic variants were confirmed using Sanger sequencing methods and evaluated by the American College of Medical Genetics (ACMG) standards.

Results: A monogenic cause of short stature was elucidated in 17 of 36 (47%) probands who were analyzed thus far. Pathogenic or likely pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR), in the extracellular matrix of the growth plate (COL1A2, MMP13, LTBP3, ADAMTS17), in the regulation and function of chondrocytes (NPR2, PTPN11, PCNT, CCDC8, CTSK, FLNB), and other genes (PTCH1, GALNS, DNACJ21, ZSWIM6, GNPTG, SLC34A3). Thereby, 10 variants were in growth plate genes, thirteen variants are homozygous and eleven variants are novel. Unexpectedly, three variants show autosomal dominant inheritance (NPR2, COL1A2, PTCH1) and one is de-novo (PTPN11). The remaining 15 probands are still being analyzed.

Conclusion: Using WES methods, we successfully elucidated the genetic cause of short stature in 47% of probands analyzed thus far. More than half of the probands harbored a pathogenic variant in genes involved in regulation and function of chondrocytes, and/or encoding components of cartilaginous matrix. These results further strength the concept, that genes affecting the growth plate (chondrocytes and the extracellular matrix) play a crucial role in growth regulation.