Prenatal diagnosis of chromosome 21q homologous rearrangement: integrated cytogenetic and molecular characterization

Abstract Background Trisomy 21, also known as Down syndrome (DS), is the most common chromosomal cause of intellectual disability. While ~ 95% of cases are due to standard trisomy 21 from meiotic nondisjunction, a minority involve structural rearrangements, such as isochromosome 21q [i(21q)]. Differentiating i(21q) from Robertsonian translocations is essential for recurrence risk assessment, as the latter often arise from parental balanced rearrangements. Molecular techniques like quantitative fluorescence PCR (QF-PCR) and STR analysis can support conventional cytogenetics in clarifying the nature and origin of structural variants. Case presentation A 36-year-old primigravida was referred for genetic counseling at 14 weeks due to high first-trimester screening risk for trisomy 21. Ultrasound showed increased nuchal translucency but no structural anomalies. QF-PCR on amniotic fluid indicated trisomy 21, and karyotyping revealed a 46,XY,i(21)(q10) constitution. STR analysis confirmed a homologous duplication of chromosome 21q of paternal origin. No mosaicism was detected in parental blood, supporting a de novo event, though germline mosaicism could not be excluded. The pregnancy was terminated at 19 weeks. Discussion This case underscores the importance of combined cytogenetic and molecular analyses for accurate diagnosis of DS due to structural anomalies. While cytogenetically similar to Robertsonian translocations, i(21q) shows full homozygosity for chromosome 21 markers and carries a distinct recurrence risk profile. Conclusions An integrated diagnostic strategy can facilitate accurate fetal aneuploidy characterization and ensure accurate risk estimation for future pregnancies, which is especially relevant when distinguishing isochromosome 21q from Robertsonian translocations, thereby improving genetic counseling for affected families.