Molecular genetic diagnosis in children with Idiopathic Short Stature: Single Center Experience

Emrullah Arslan; Solmaz Aslı Ece; Enise Avci; Balkı Hanife Gul; Kızılay Deniz Ozalp; Arzu Jalilova; en Er; Damla Goksen; Samim Ozen; Sukran Darcan

Introduction: Idiopathic short stature(ISS) refers to children who are short because there is no identifiable defect in the growth hormone (GH)/insulin-like growth factor(IGF) axis and no other endocrine or genetic disorders. The genetic etiology of ISS in children was investigated in this study using targeted next-generation sequencing(NGS).

Method: Eighty patients with short stature of unknown etiology were included in the study. Variants in 23 genes associated with ISS were screened with a panel of targeted NGS.

Results: Aclinical variant was detected in46% of the patients (Group 1); of these, 6 (7.5%) pathogenic, 12 (15%) likely pathogenic, and 19 (24.0%) variants of uncertain significance (VUS), and 54% (Group 2) no variant detected. At the time of admission, height SDS of group 1 (-3.1±0.9) was lower than that of group 2 (-2.5±0.66) (p:0.004). While the rate of growth hormone use was 76% in group 1, it was 64% in group 2. In addition, the first-year of group 1 after growth hormone treatment was -2,7 (-3.1/-2), group 2 -2 (-2.48/-1.5) (p:0.01). The final height SDS of group1 was -2.25 (-2.9/-2.1), while it was -1.7 (-2.1/-1) lower than that of group 2 (p:0, 04). In the first year after treatment, IGF-1SDS was 1.56 (0.4/4) higher in group 1 and 0.64 (-0.8/1.8) higher than group 2 (p:0.018). Characteristics of variants classified as likely pathogenic/pathogenic are summarized in Table 1.

Table 1: Characteristics of Likely Pathogenic or Pathogenic Variants
Gene	Variant	Zygosity	ACGM	Clinic
FGFR3	c.1620C>A	Het	Pathogenic	Hypochondroplasia
IFT57	c.569T>C	Hom	Likely Pathogenic	Orofasiodigital Syndrome Type8
ANKRD11	c.1372C>T	Het	Pathogenic	KBG Syndrome
COL2A1	c.2356-3C>G	Het	Likely Pathogenic	Spondyloepiphyseal Dysplasia Congenita
TRPV4	c.838G>A	Het	Pathogenic	Spondylometaphyseal Dysplasia, Kozlowski Type
CSGALNACT1	c.1151C>G	Hom	Likely Pathogenic	Mild Skeletal Dysplasia, Joint Looseness, Advanced Bone Age Syndrome
GYS2	c.1451G>C	Hom	Pathogenic	Glycogen Storage Type0
HMGA2	c.30delG	Het	Likely Pathogenic	Silver Russell Syndrome
GHR	c.674A>G	Het	Likely Pathogenic	GH Resistance Tip2
AIRD2	c.5371_5372del	Het	Likely Pathogenic	Coffin Siris Syndrome
PCNT	c.8326C>T	Het	Pathogenic	Microcephalic Osteodysplastic Primordial Dwarfism Type2
GLI2	c.3799C>G	Het	Likely Pathogenic	Culler Jones Syndrome
FGFR2	c.24+2T>G	Het	Likely Pathogenic	Apert Syndrome
ACAN	c.7122C>A	Het	Likely Pathogenic	Advanced Bone Age, Early Osteoarthrosis, Osteochondrosis Syndrome
PROKR2	c.254G>A	Het	Likely Pathogenic	Pituitary Insufficiency
FBN1	c.5351A>G	Het	Likely Pathogenic	Acromicric Dysplasia
FGFR3	c.445+2_445+5del	Het	Likely Pathogenic	Hypochondroplasia
OBSL1	c.1273dupA	Hom	Pathogenic	3M Syndrome

Conclusion: TargetedNGS panels can be used successfully to brighten the genetic cause in patients with idiopathic short stature.In patients with mild and heterogeneous clinical findings, the treatment andfollow-up of the cases can be managed more accurately with NGS panels and genetic diagnosis.

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