Familial Robertsonian Translocation, rob(14;21), with High Risk for Down Syndrome

Area of Science:

• Genetics
• Human Genetics
• Reproductive Genetics

Background:

• Robertsonian translocations are common chromosomal rearrangements.
• Female carriers of Robertsonian 14;21 translocation have an elevated risk of trisomy 21 offspring.
• Understanding the mechanisms behind translocation inheritance is crucial for genetic counseling.

Purpose of the Study:

• To investigate the genetic basis of an unusually high incidence of translocation trisomy 21 in a large Omani family.
• To analyze meiotic recombination patterns in individuals with Robertsonian 14;21 translocation.
• To identify potential genetic variants contributing to nondisjunction events.

Main Methods:

• Microsatellite marker analysis of chromosomes 14 and 21 to study meiotic recombination.
• Whole genome sequencing (WGS) of the carrier mother.
• Comparative analysis with a family exhibiting free trisomy 21.

Main Results:

• A significant increased risk for translocation trisomy 21 offspring in the core family.
• Nondisjunction occurred during the first meiotic division (MI) in all affected cases.
• Unusual crossover patterns, including double crossovers, were observed on chromosome 21, differing from free trisomy 21 cases.
• WGS did not identify known pathogenic variants associated with meiotic dysfunction.

Conclusions:

• The study reports a novel instance of chromosomal transmission ratio distortion.
• An atypical meiotic recombination pattern was observed between the translocation chromosome and free chromosome 21.
• Further research is needed to elucidate the precise mechanisms underlying this phenomenon.