6513 Identification of pathogenic ACAN variants in healthy children with normal height and advanced bone age

Abstract Disclosure: M. Hernandez: None. N. Unanue: None. V. Gallardo: None. H. Van duyvenvoorde: None. M.V. Mericq: None. Background/rationale: Linear growth is determined by proliferation and differentiation of growth plate (GP) chondrocytes. The main proteoglycan component of the extracellular matrix of GP is ​​aggrecan, encoded by the ACAN gene. Homozygous pathogenic variants have been reported in patients with spondylo-metaphysial dysplasia. Heterozygous pathogenic variants are associated with non-syndromic short stature of pre or postnatal onset, in most cases with advanced bone age, early-onset dissecting osteoarthritis, and some other dysmorphic features. Hypothesis Children with normal height and significant advanced bone age can present pathogenic variants in the ACAN gene. Patients and methods: Healthy prepubertal children referred for height evaluation because of advanced bone age (≥ 2 SDS using Bayley Pineau, validated using Bonexpert) in combination with normal height (± 2 SDS) and BMI (15th-85th centile ) were included, after signing informed consent. We excluded puberty by clinical Tanner staging, CAH or premature adrenarche (DHEAS > 40 micr/dl RIA), GH excess or thyroid disorders and medications that could advance bone age. Genomic DNA was isolated from peripheral blood using QIAamp DNA Mini kit (Qiagen, Germany). Sequencing was performed on an Illumina platform using the Agilent enrichment kit SureSelectXT Clearseq Inherited Disease Panel (IDP). SNV (single nucleotide variant and CNV (copy number variant) data analysis of all coding exons of the ACAN gene including +/- 20 nucleotides of flanking intron sequences was performed, with exception of the complex Variable Number of Tandem Repeats (VNTR) structure in exon 12. Results : 17 prepubertal Caucasian children (2 females) were genotyped at a mean age 7.7 ±1.8 years, a height of -0.47±0.89 SDS, a BMI of -0.05 ±1.19 SDS, a mid-parental height of -0.34 ±0.59 SDS and mean difference between height and MPH 0.28±0.77 SDS . None of these children had a pathogenic ACAN variant. Conclusion: this study suggests that pathogenic ACAN varians appear not to be a prevalent cause of advanced bone age in healthy prepubertal children. Follow-up of this group of patients will provide us with more information on the impact of the advanced bone age on final height. Dependent on the final height outcome, additional genetic investigations can be considered. Presentation: 6/3/2024