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.