ESPE Abstracts (2019) 92 P1-362

1Department of Science's Health, Meyer Children's University Hospital, Florence, Italy. 2Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy. 3DeDepartment of Medicine and Medical Biotechnologies, University Federico II of Naples (Italy) and CEINGE Advanced Biotechnologies, Naples, Italy. 4Department of Medicine and Medical Biotechnologies, University Federico II of Naples (Italy) and CEINGE Advanced Biotechnologies, Naples, Italy. 5Medical Genetics Unit, Dpt. Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy

Background/Aims: Short stature is a common reason for presentation to paediatric endocrinology clinics. Getting to a diagnosis of short stature is a multi-step, complex process of tests that only in a few cases save a diagnosis. As genetic plays a strong role in height, we sought to identify known and novel genetic causes of short stature.

Methods: We recruited 18 children with severe short stature, we conducted whole exome sequencing (WES) on trio (both parents and their affected child) to detect de novo, homozygous and compound heterozygous variants; our aim was to extend the identification of the genetic bases of short stature by searching for know and novel candidate genes/pathways. We used an analysis pipeline to identify both rare and polymorphic genetic variants that cause the short stature.

Results: Clinical exome sequencing was performed on 18 patients with suspected genetic conditions of short stature, belonging to 11 families and was extended on theira parents. We identified a known genetic disease cause in 7/18 patients, corresponding to a molecular diagnostic rate of 39%. These included cases of: i) Hypochondroplasia, ii) Hypoparathyroidism-retardation-dysmorphism syndrome, iii) Microcephalic osteodysplastic primordial dwarfism, type II, iv) Isolated growth hormone deficiency due to defect in GHRH, v) Hypothyroidism central, vi) Partial growth hormone deficiency, vii) 1 case of delayed puberty, in which we have found mutation in IGSF10 gene. For the remaining patients (11/18 patients), we have generated lists of candidate variants. In the most patients with growth hormone deficiency, we identified a polymorphic intronic variant, that influences GH1 mRNA expression and secretion, together with other polymorphic or rare variant/s in other genes responsible to GH secretion. These finding highlights that despite the diagnosis in some patients is evident, the identification of genetic cause is very complicate: it's necessary evaluate the contribution of more variants also in genes not yet characterized.

Conclusions: These finding could be helpful for identifying causal functional variants and increasing our basic knowledge; our results highlight that WES provide new insights useful for the genetic diagnosis of short stature, as well as for the identification of biological pathways that will be potentially targeted by new therapeutic strategies. Additionally, the understanding of genetic bases of short stature phenotype will be useful to direct treatment decisions surrounding use of growth hormone or insulin-like growth factor 1 therapy.

Volume 92

58th Annual ESPE

Vienna, Austria
19 Sep 2019 - 21 Sep 2019

European Society for Paediatric Endocrinology 

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