Commentary on "Genetic evaluation using next-generation sequencing of children with short stature: a single tertiary-center experience"

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Ann Pediatr Endocrinol Metab. 2024;29(1):1-2
Publication date (electronic) : 2024 February 29
doi :
Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
Address for correspondence: Hye Young Jin Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 150, Seongan-ro, Gangdong-gu, Seoul 05355, Korea Email:

Genetic factors play a considerable role in determining the height of an individual; however, growth is a complex process influenced by multiple factors [1]. Initially, research exploring genetic variations in the somatotropic axis revealed defects in only a small proportion of cases [2]. Large-scale genomic analysis has contributed to an improved understanding of the genetic complexity of short stature, showing that height is a polygenic trait [3]. Nevertheless, next-generation sequencing (NGS) has identified monogenic causes of short stature. Numerous genetic variations affecting growth plate function, such as multiple hormones, paracrine factors, extracellular matrix molecules, and intracellular proteins have been discovered because the linear growth of children results from chondrogenesis at the growth plate [4,5]. In general, genetic analysis is indicated in patients with a clinical suspicion of monogenic disorders, such as severe short stature (below -3 standard deviations of their height score), microcephaly, or relative macrocephaly, intellectual disability, dysmorphic features, disproportional short stature, positive family history, and low birth weight (small for gestational age without catch-up growth) [6,7].

In the case of familial short stature, many individuals with familial short stature are likely to exhibit polygenic short stature, characterized by inherited common gene variants. Genetic investigation is not recommended in children with mild familial short stature without any additional abnormal clinical features [1,8]. However, if the height of the patient is more profound with both parental heights in a low percentile or a similar height deficit as one parent, there maybe a presence of a single genetic defect [9]. If a patient exhibits short stature while both parents have normal height, the cause could be a genetic mutation occurring de novo or in an autosomal recessive fashion. Alternatively, it might be a constitutional delay of growth and puberty, especially if bone age is delayed, predicted adult height is close to midparental height, and there is a family history of delayed puberty [9]. The diagnostic rates from previous NGS studies on short stature varied depending on the characteristics of the study population, demonstrating higher diagnostic yields in severe short stature [10]. Genetic defects are more frequently detected in syndromic short stature or children born small for gestational age [11,12]. In a recent study conducted at a single tertiary center, a diagnostic rate of 40.5% was observed, with 15 pathogenic or likely pathogenic variants from 13 different genes found in 37 patients [13]. It is important to note that the inclusion criteria of this study aligned with the indications for genetic analysis mentioned earlier. However, the study has limitations, including a small number of patients, potential selection bias, and nonuniformity of genetic testing methods.

With advances in genomic technology, clinical genetic evaluation has become an important tool for elucidating the causes of growth disorders. We can predict responsiveness to growth hormone therapy, and contraindications for growth hormone therapy can be confirmed in some cases through a definitive molecular diagnosis. Furthermore, pre-existing but undiagnosed syndromic disorders can be identified, and morbidities that may arise in the future can be predicted and addressed properly [14,15]. Genetic counseling should also be appropriately conducted after a molecular diagnosis.

The diagnostic yield remains low, despite the identification of many monogenic causes of short stature. Genes responsible for growth disorders are of great interest and continue to be under investigation. However, the pathogenicity of certain genetic variants remains uncertain, and the interpretation of multiple coexisting genetic variations can be challenging. Noncoding variants and epigenetic changes are not covered by the NGS panels for short stature or exome sequencing. Specific phenotypes can offer clues for genetic defects that can be detected through specific genetic testing.

Genetic studies are essential to progress from clinical phenotypes and hormonal assessments to more precise genetic diagnoses and managements [8]. The careful selection of patients is crucial for increasing diagnostic yield and reducing unnecessary expenses and effort.


Conflicts of interest

No potential conflict of interest relevant to this article was reported


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