ESPE2024 Poster Category 2 Late Breaking (107 abstracts)
High Frequency of Copy Number Variations as Genetic Causes of Failure to Achieve Catch-Up Growth in Small for Gestational Age Children: A Multicenter Study in Korea
Yena Lee 1 , Min Jae Kang 2 , Hwal Rim Jeong 3 , Eun Young Kim 4 , Eu-seon Noh 5 , Hye young Jin 5 , Eun Byul Kwon 6 , Hye Jin Lee 7 , Young-Jun Seo 8 , Nan Young Kim 9 , Sangkyoon Hong 9 & Il-Tae Hong 2
1Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang-si, South Korea. 2Department of Pediatrics, College of Medicine, Hallym University, Chuncheon, South Korea. 3Department of Pediatrics, College of Medicine, Soonchunhyang University, Cheonan, South Korea. 4Department of pediatrics, Chosun University Hospital, Gwang-ju, South Korea. 5Department of Pediatrics, Kangdong Sacred Heart Hospital, Seoul, South Korea. 6Department of Pediatrics, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, South Korea. 7Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, South Korea. 8Department of Pediatrics, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, South Korea. 9Hallym Institute of Translational Genomics and Bioinformatics, Hallym University Medical Center, Anyang-si, South Korea
Background: Small for gestational age (SGA) children are defined by birth weight and/or length at least 2 standard deviations (S.D) below the population mean for gestational age. Up to 90% of these infants experience catch-up growth within the first two years of life; however, 10-15% fail to do so, remaining short at age 2 (SGA-SS). The etiology of failure to achieve catch-up growth remains largely unknown.
Methods: This study aim ed to elucidate the genetic causes of failure to achieve catch-up growth in SGA children within the Korean population. Subjects were recruited from multicenter SGA-SS cohorts spanning seven university hospitals in South Korea. A total of 157 children were included, and whole exome sequencing was conducted. Copy number variations (CNVs) were identified from exome sequencing data and validated using chromosomal microarray (CMA). Genetic variants were classified according to ACMG guidelines.
Results: Genetic variants were identified in 24 out of 157 (15.3%) children. Among these, 22 children harbored genetic abnormalities associated with pre- and postnatal growth retardation, while two had unrelated secondary findings. The majority of genetic abnormalities associated with SGA-SS were copy number variations (15/22, 68.2%). Notably, 22q11.2 microdeletion syndrome was observed in seven children (7/22, 31.8%), characterized by mild dysmorphic features without significant intellectual disability or congenital anomalies, potentially delaying diagnosis. Seven children (7/22, 31.8%) exhibited eight sequence variants in growth-related genes, with three classified as pathogenic, five as likely pathogenic, and one as a variant of uncertain significance (VUS). Genes implicated in skeletal dysplasia were frequently identified in SGA-SS cases, including ACAN, COL2A1, and SLC26A2. A pathogenic variant in PLAG1, associated with Silver-Russell syndrome, was identified in an 11-year-old girl, while a likely pathogenic variant in PIK3R1 causing SHORT syndrome was also detected.
Conclusion: The genetic basis of failure to achieve catch-up growth in SGA-SS children is heterogeneous. Our findings underscore the significance of copy number variations in this condition. The broad phenotypic spectrum of 22q11.2 microdeletion syndrome, as evidenced by our cases with mild dysmorphic features, suggests its consideration in the differential diagnosis of SGA-SS.
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