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

Robertsonian translocations resulting from the fusion of two acrocentric chromosomes are the most common chromosomal rearrangements in healthy individuals. Female carriers of a Robertsonian 14;21 translocation have a 10% risk for a liveborn with trisomy 21.

The study is based on a large family from Oman with eight offspring with translocation trisomy 21 (rob(14;21)(q10;q10),+21). The core family had nine live births, of which five were affected by translocation trisomy 21, two are monozygotic twins. The meiotic recombination pattern was analyzed by microsatellite markers covering chromosomes 21 and 14. For comparison, meiotic recombination was studied in an Arab family with three offspring with trisomy 21. In addition, in the mother of the core family whole-genome sequencing (WGS) was performed to look for possible variants involved in this process.

Apart from the core family, there are three other related families with one affected child each. The increased risk for a child with translocation trisomy 21 in the core family is significant. In all cases, the nondisjunction took place at the first meiotic division (MI). Crossovers along chromosome 21 were observed in all affected children, in 2 cases a double crossover in the proximal part of chromosome 21. This pattern is completely different to that of the family with free trisomy 21. WGS did not reveal known pathogenic/likely pathogenic variants related to meiotic dysfunction.

To the best of our knowledge, such a chromosomal transmission ratio distortion has not been reported so far. In addition, meiotic recombination between the translocation chromosome and free chromosome 21 showed an unusual pattern.