The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature
Language English Country Switzerland Media print-electronic
Document type Journal Article
PubMed
37019085
DOI
10.1159/000530521
PII: 000530521
Knihovny.cz E-resources
- Keywords
- GH-IGF-1 axis, Genetics, Growth plate, Short stature, Small for gestational age,
- MeSH
- Child MeSH
- Gestational Age MeSH
- Infant, Small for Gestational Age MeSH
- Insulin-Like Growth Factor I MeSH
- Humans MeSH
- Human Growth Hormone * genetics MeSH
- Dwarfism * MeSH
- Infant, Newborn MeSH
- Growth Disorders genetics diagnosis MeSH
- Short Stature Homeobox Protein MeSH
- Silver-Russell Syndrome * genetics MeSH
- Body Height genetics MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Insulin-Like Growth Factor I MeSH
- Human Growth Hormone * MeSH
- Short Stature Homeobox Protein MeSH
- SHOX protein, human MeSH Browser
INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.
References provided by Crossref.org
Monogenic causes of familial short stature
Etiology of combined pituitary hormone deficiency: GNAO1 as a novel candidate gene
Editorial: Short stature: beyond growth hormone
Analysis of children with familial short stature: who should be indicated for genetic testing?