ESPE Abstracts

Introduction: Linear growth is a complex process involving the interplay of genetic, epigenetic, and environmental factors. Current knowledge sheds importance to the GH-IGF-1 axis, chondrocyte regulation and extra-cellular matrix in the growth plate, and other fundamental intracellular processes. Despite these advancements, the genetics of short stature are not fully understood. This study aims to contribute by investigating a unique cohort of children from consanguineous families from Sulaimani, Iraq.

Patients and Methods: Fifty-one probands (30 females) with height ≤-2.3SD, examined at the paediatric endocrine outpatient clinic, Dr. Jamal Paediatric teaching hospital between January 2018 and February 2020, were included in the study. Their median height was -3.3 SD (IQR -4.15SD to -3SD) and median age 8 years (IQR 5-10). DNA of the proband, both parents, and health/affected siblings (when available) was obtained with informed consent. Probands’ DNA was analyzed by Whole Exome Sequencing. Data was processed by a bioinformatic pipeline and variants were filtered using variant analysis software. Prioritized potentially pathogenic variants were evaluated by the ACMG standards and confirmed using Sanger sequencing. Probands without detected causal variant further underwent MLPA and arrayCGH testing to look for Silver-Russell Syndrome and micro-deletions /micro-duplications respectively.

Results: A pathogenic cause of short stature was elucidated in 33/51 (65%) probands. In addition, one proband had uniparental isodisomy of chromosome1 of uncertain significance. Two probands had Silver-Russell and one had DiGeorge syndrome respectively. In the other 30 probands, pathogenic or likely pathogenic variants (17 novel) were found in genes involved in the GH-IGF-1 axis (GHR, SOX3), the thyroid axis (TSHR), the growth plate extracellular matrix (COL1A2, COL10A1, FLNA, FN1, MMP13, LTBP3), the regulation/function of chondrocytes (DYM, NPR2, PTPN11, CTSK, SHOX), cell and DNA/RNA replication and repair (LIG4, CCDC8, GZF1, DNAJC21, PCNT, CFAP410), transport (SLC34A3, SLC7A7) and enzyme coding genes (CYP27B1, GALNS, GNPTG). Majority of variants (24) are homozygous, while 6 are autosomal dominant (NPR2, COL1A2, FN1, SHOX), including de-novo variants (PTPN11, FLNA).

Conclusion: The genetic cause of short stature was elucidated in 65% of probands in a unique cohort from a highly consanguineous region. The spectrum of causative genes is varied when comparing to non-consanguineous regions. As expected, most variants were recessive. Many cases of syndromic short stature were diagnosed even though they were initially referred as idiopathic short stature with either mild or undocumented phenotypic features, enabling active screening for possible concomitant conditions and timely management.