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Fragile X syndrome in two siblings with major congenital malformations
P F Giampietro1, B R Haas, E Lipper
1Division of Medical Genetics, New York Hospital, Cornell University Medical Center, New York 10021, USA.
Insights
Two brothers diagnosed with both fragile X syndrome and VACTERL-H syndrome exhibited large triplet repeat expansions in the FMR1 gene. This genetic finding suggests a potential link between fragile X mutations and VACTERL-H syndrome.
Area of Science:
- Genetics
- Developmental Biology
- Clinical Medicine
Background:
- Fragile X syndrome is a genetic disorder caused by expansions in the FMR1 gene.
- VACTERL-H syndrome is a complex congenital disorder characterized by a spectrum of abnormalities.
Observation:
- Two brothers presented with overlapping features of both fragile X syndrome and VACTERL-H syndrome.
- Clinical manifestations included cleft lip/palate, cardiac defects, hypoplastic thumb, tracheoesophageal fistula, esophageal atresia, and vertebral abnormalities.
- Genetic analysis revealed large triplet repeat expansions in the FMR1 gene and methylation mosaicism in both siblings.
Findings:
- High-resolution chromosome analysis confirmed a 46, XY karyotype in both affected individuals.
- PCR and Southern blot analyses identified significant expansions of CGG repeats in the FMR1 gene, consistent with fragile X syndrome.
- Enzyme kinetic studies showed differential iduronate sulfatase activity between the siblings, suggesting potential gene interactions.
Implications:
- This case report highlights a potential co-occurrence or genetic interaction between fragile X syndrome and VACTERL-H syndrome.
- Investigating the molecular mechanisms underlying this co-occurrence may reveal novel insights into gene regulation and developmental pathways.
- Further research is warranted to explore the genetic basis and clinical implications of this combined presentation.
Abstract:
We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2 1/2, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46, XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed.