Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations

Abstract

Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes.

Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

“…It has been suggested that 70% of complex rearrangements are associated with a normal phenotype [Pellestor et al, 2011]. Consistent with this, we identified X chromosomal chromothripsis in a woman who showed no apparent clinical features except for ovarian dysfunction and hyperthyroidism [Suzuki et al, 2016]. The relatively mild phenotype of this woman can be explained by the selective inactivation of the rearranged X chromosome.…”

Chromoanagenesis: a piece of the macroevolution scenario

“…Some chromoanagenesis events arise de novo, but accumulating data on familial chromoanagenesis-mediated rearrangements have validated the notion of the heritability of chromoanagenesis-mediated genomic alterations [12,34]. Recent reports have provided evidence that chromoanagenesis can operate in human germline cells and during early embryonic development [35][36][37], strongly suggesting that chromoanagenesis could be more common than anticipated in gametes and preimplantation embryos.…”

Catastrophic cellular events leading to complex chromosomal rearrangements in the germline

“…Our recent study exemplified the 'recurrent DNA damage' model (7). In this study, we identified an X chromosomal rearrangement in a girl clinically diagnosed with Turner syndrome.…”

“…The phenotypes of germline X chromosomal rearrangements are ascribable to chromosomal imbalances and dysregulation of X chromosomal genes that escape inactivation. Additionally, complex X chromosomal rearrangements may perturb the DNA methylation status in some genes that usually escape X inactivation (7). It is worth mentioning that germline complex rearrangements are not necessarily pathogenic.…”

“…In contrast to the severe pathogenicity of most germline complex rearrangements in autosomes, rearrangements involving the X chromosome has been identified in women with ovarian dysfunction as the sole recognizable clinical feature . In addition, a complex X chromosomal rearrangement was identified in a girl with an unmasked recessive mutation in CSF2RA and short stature .…”