Robertsonian translocation occurs about 1 in 1,000 newborn babies. We reported a family with Robertsonian translocation, the parents were cousins both with Robertsonian translocation, and the son had a novel karyotype 44,XY,der(14;15)(q10;q10),der(14;15)(q10;q10).
There are many such rearrangements of different species in natural populations similar to humans. The fitness of the carriers of Robertsonian translocation is reduced, but Robertsonian translocation could facilitate evolution of animals and humans [9–10]. Robertsonian rearrangements could improve polymorphisms in natural populations, provide individuals for natural selection and even form a new species [11–12]. Homozygous Robertsonian translocations have been reported with balanced chromosomal sperms [13]. A group of same type of Robertsonian translocation carriers could theoretically form a new human subspecies with 44 chromosomes by long-term isolation.
Robertsonian translocation carriers can produce six types of gametes. At the end of meiosis I, segregation of the translocated and nontranslocated chromosomes from the two different chromosome pairs involved leads to the formation of either balanced gametes via alternate segregation or unbalanced gametes via adjacent segregation during anaphase [1]. Meiotic tetravalent configuration tends to segregate in alternate way, resulting in preferential production of normal/balanced spermatozoa. However, certain percentages of unbalanced gametes derived from adjacent segregation are also produced, leading to the increased risk of miscarriage and chromosomally unbalanced fetus. Although most carriers of Robertsonian translocation have normal lifespan and normal phenotype, they have an increased risk of producing unbalanced gametes, offsprings with trisomies and pregnancy loss.
UPD can be associated with human diseases through homozygosity for an autosomal recessive trait, disruption of the normal allelic expression of genes that undergo genomic imprinting, or due to incomplete (cryptic) trisomic rescue [14]. Most often UPD is considered as a molecular genetic problem, but in some latest researches, it is affirmed and substantiated by corresponding data that UPD is a chromosomic disorder in the first place [5].
The association between Robertsonian translocations and UPD is due to malsegregation and the consequent increased risk of aneuploid gametes production. Adjacent 2 : 1 segregation generates two types of disomic and two types of nullisomic gametes, giving rise, after fertilization, to trisomic and monosomic zygotes respectively. Subsequently, a post-zygotic correction of the aneuploidy can occur, either by duplication (in monosomy) or loss (in trisomy) of the homologue chromosome involved in the aneuploidy. This mechanism of ‘aneuploidy rescue’ can generate a UPD condition in the conceptus [6].
Some researchers suggested that UPD testing must be performed to establish the correct fetal prognosis in the cases of Robertsonian translocations involving chromosomes 14 and 15, since they harbour imprinted genes and uniparental derivation is associated with abnormal phenotypes: maternal and paternal UPD 15 give rise to Prader–Willi and Angelman syndromes respectively; maternal and paternal UPD 14 give rise to Temple and Kagami-Ogata syndromes respectively [7–8]. However, others did not recommend prenatal testing for UPD for these carriers [15].
Prader-Willi syndrome is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from imprinting defects and maternal UPD [16]. Temple syndrome is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14, an isolated methylation defect of the MEG3-DMR or paternal deletion of 14q32 [17].
Prader-Willi syndrome and Temple syndrome share several clinical features in infancy and childhood, notably neonatal hypotonia, feeding difficulties in early infancy, childhood overweight, short stature, small hands and feet, and developmental delay [7, 18]. These syndromes are imprinting disorders main caused by UPD, so related inspections must be performed in the cases of Robertsonian translocations involving chromosomes 14 and 15 [7–8].
UPD can be grouped into cases with pure isodisomy, pure heterodisomy and such with mixed iso-/heterodisomy. UPD can be detected by SNP-based CMA technology and Trio-WES. SNP-based CMA consist of sets of oligonucleotides specific for polymorphisms in the genome. It must be stressed, that in SNP-based CMA only isodisomy can be detected and is normally blind for heterodisomy. Trio-WES can detect isodisomy and heterodisomy UPD [14].
In this family, no isodisomy or heterodisomy UPD, no pathogenic mutations or homozygous recessive pathogenic genes were detected by CMA and Trio-WES. Prenatal ultrasound examination revealed no dysmorphisms or IUGR.
At 38 weeks of gestation, a 3100-g male infant was born by cesarean section. Apgar scores were 8/9/9.The infant received a complete physical examination with normal findings.
In a sense, the carrier of homozygous Robertsonian translocation can be regarded as a “normal” diploid individual (n = 22). He can produce “normal” haploid sperm [1]. Therefore, we think that the probability of UPD in his offsprings will be lower than that of Robertsonian translocation carriers’ offsprings.
The opposite concept of Robertsonian translocation is Robertsonian fission or centromere fission. Robertsonian fission is rarely reported. Robertsonian fission can provide material for evolution, and centromere fission is the probable trigger of CIN and early carcinogenesis [10, 19–20].
In this family, we observed Robertsonian fission of the human chromosome. This is the first report of Robertsonian fission in a homozygous Robertsonian translocation family. The UPD resulting from the loss of the Robertsonian translocation chromosome and the monosomic rescue can be excluded because no abnormality was found by CMA and Trio-WES [14].
The carriers of homologous Robertsonian translocation are associated with infertility because of the production of disomic or nullisomic gametes in gametogenesis. In theory, there is no chance for homologous Robertsonian translocation carriers to have a normal karyotype embryo unless there is UPD of the homologous Robertsonian translocated chromosomes. Literature search showed that a homologous 14;14 Robertsonian translocation carrier had 13% normal sperms and had a child with normal chromosome through IVF [21].
In terms of the mechanics of Robertsonian fission, the homozygous Robertsonian translocation carrier of our study is different from the homologous Robertsonian translocation carrier. The Robertsonian fission of the homologous Robertsonian translocation carrier occurred during the stage of gamete formation. Judging from chimerism ratio, Robertsonian fission of the homozygous Robertsonian translocation carrier perhaps occurred when the oosperm division began.