Endocrine Abstracts

JOINT2816

Objective: Approximately 10%–15% of small for gestational age (SGA) infants fail to achieve catch-up growth by age 2 years, resulting in persistent short stature (SGA-SS). The genetic mechanisms of this condition remain poorly understood. This study aimed to systematically delineate the genetic landscape of Chinese SGA-SS children through integrated clinical phenotypes and multi-omics data, and to assess the diagnostic utility of a tiered genetic testing strategy.

Methods: A cohort of 97 SGA-SS children (birth length/weight < 10th percentile, height standard deviation score [Ht-SDS] <−2 S.D./3rd percentile at 2 years) underwent a stratified genetic evaluation. Subjects with a Netchine-Harbison Clinical Scoring System (NH-CSS) ≧4 or strong clinical suspicion of Silver-Russell syndrome (SRS) underwent first-line methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Those with NH-CSS ≤3 underwent whole-exome sequencing (WES). Undiagnosed cases were further investigated via cross-validation (reciprocal MS-MLPA and WES testing). All variants were classified according to ACMG guidelines and confirmed via Sanger sequencing. A cohort of 57 pediatric patients receiving 12-month growth hormone (GH) therapy was stratified by genetic testing results into two subgroups: a genetically positive cohort (n=22) and a genetically negative cohort (n=35).

Results: Genetic etiologies were identified in 41.2% (40/97) of patients. The pathogenic spectrum comprised:

1. Intracellular signaling pathways/cellular processes defects (14/40, 35%), involving 12 genes (PTPN11, KMT2D, MAP2K1, SRCAP, CHD7, BPTF, RAD21, KDM5C, NSD2, DYRK1A, ACTB, FAM111A).

2. Imprinting disorders 25% (10/40, 25%), including 9 SRS (11p15 hypomethylation/UPD7) and 1 Temple syndrome (UPD14).

3. 6 cases harbored variants in Paracrine factors/extracellular matrix-related gene variants (6/40,15%): ACAN, ROR2, NPR2, FGFR3.

4. Copy number variants (CNVs) (6/40, 15%).

5. Chromosomal abnormalities (4/40, 10%)

Notably, three novel pathogenic variants (ROR2 c.1384C>T, ACTB c.1104delC, and DYRK1A c.1702_1705del) were identified. The genetically diagnosed group exhibited more severe postnatal growth retardation (baseline Ht-SDS: −3.49±1.18 vs. −2.63±0.692, P < 0.01), though GH therapy response (ΔHt-SDS) showed no intergroup difference (P=0.694).

Conclusion: This multi-omics investigation achieved a 41.2% diagnostic yield in Chinese SGA-SS, revealing intracellular signaling/cellular process and imprinting disorders as predominant mechanisms. Our tiered diagnostic approach (methylation analysis combined with WES) optimized detection efficacy, while three novel variants expanded the mutational spectrum. Despite genotype-specific growth patterns, GH responsiveness appears independent of specific genetic etiology, though larger validation studies are needed.