Detection of Del/Dup Inside SHOX/PAR1 Region in Children and Young Adults with Idiopathic Short Stature.

Jera Stritar,Tinka Hovnik,Katarina Trebušak Podkrajšek,Maja Ficko,Lana Stavber,Tadej Battelino,Primož Kotnik

doi:10.3390/genes12101546

Jera Stritar, Tinka Hovnik + Show 5 more

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https://doi.org/10.3390/genes12101546

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Abstract

Short stature is a common growth disorder defined as a body height two standard deviations (SD) or more below the mean for a given age, gender, and population. A large part of the cases remains unexplained and is referred to as having idiopathic short stature (ISS). One of the leading genetic causes of short stature is variants of short stature homeobox-containing gene (SHOX) and is considered to be responsible for 2–15% of ISS. We aimed to analyse the regulatory and coding region of SHOX in Slovenian children and young adults with ISS and to investigate the pathogenicity of detected variants. Our cohort included 75 children and young adults with ISS. Multiplex ligation-dependent probe amplification (MLPA) was performed in all participants for the detection of larger copy number variations (CNVs). Sanger sequencing was undertaken for the detection of point variants, small deletions, and insertions. A total of one deletion and two duplications were discovered using the MLPA technique. Only one of these four variants was identified as disease-causing and occurred in one individual, which represents 1.3% of the cohort. With Sanger sequencing, two variants were discovered, but none of them appeared to have a pathogenic effect on height. According to the results, in the Slovenian population of children and young adults with ISS, SHOX deficiency is less frequent than expected considering existing data from other populations.

Highlights

Short stature is a frequent developmental condition in childhood and is one of the most common reasons for visiting paediatric endocrinologists
Bone age (BA) compared to the chronological age was delayed in 53% and advanced in 13% of the participants
We identified altogether five alternations in the stature homeobox-containing gene (SHOX) gene region including noncoding enhancer regions, of which one was present in three different subjects

Summary

Introduction

Short stature is a frequent developmental condition in childhood and is one of the most common reasons for visiting paediatric endocrinologists. The prevailing pathological causes of short stature are growth hormone (GH) deficiency, genetic disorders, hypothyroidism, and celiac disease. In 50–90% of the cases, no obvious pathological cause is found, so they are classified in the group of normal short stature–familial short stature, constitutional delay of growth and puberty, or idiopathic short stature (ISS). According to the Consensus Statement from 2008, ISS is defined as a height two standard deviations (SD) or more below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine (e.g., GH deficiency, hypothyroidism, Cushing syndrome, precocious puberty), nutritional, chromosomal abnormalities (e.g., Turner syndrome), evident skeletal dysplasia, or other genetic syndromes (Noonan, Silver–Russell, Prader–Willi) [3]. ISS diagnosis is complex and based on medical history, physical examination, standard laboratory tests, and genetic analysis. There is still a large proportion of those in whom the specific genetic cause by standard and existing genetic analysis remains undetermined

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