ABSTRACT

Pericentric inversions arise from double breaks on opposite arms of the chromosome, followed by 180° rotation and reintegration of the broken segment. Carriers of an inversion are mostly phenotypically healthy. However, they may have some clinical implications, including reproduction anomalies due to imbalanced gamete production. Here, we highlighted the phenotypical variability of X chromosome inversions by reporting a case. The female proband who had recurrent spontaneous abortions was admitted to the Medical Genetics polyclinic. After clinical evaluation, conventional Giemsa-banded karyotyping was performed. The result was 46,X,inv(X)(p11.2q26). Segregation analysis of the family members revealed that she inherited the pericentric inversion from her father and passed it on to her daughter. Detailed genetic counseling was provided to the family. The significance of X chromosome pericentric inversions in the literature was discussed with regard to their phenotypical relevance to enhance our understanding of clinical variability caused by chromosomal inversions.

Case Presentation

A 35-year-old female patient was admitted to the medical genetics polyclinic with a complaint of recurrent pregnancy losses (in November 2021). She had five spontaneous pregnancies. The first two resulted in two healthy children who were born during the term. However, the next three pregnancies resulted in an abortion at 5, 7, and 7 weeks, respectively. She had no other health complaints, and there was no consanguinity. Physical examination revealed a mild/moderate symmetrical short stature (measured height was 158 cm). Her husbands evaluation revealed no symptoms or findings. To understand the etiology of the habitual abortus, karyotype analysis from peripheral blood was performed on both spouses. Metaphase chromosomes obtained from peripheral blood lymphocyte cultures were evaluated using high-resolution G-banding techniques; using the Leica Biosystems imaging system (IL, USA). At least 10 karyotypes at the 450-600 band resolution level were analyzed, and at least 50 metaphase cells were counted in each specimen. Results were reported according to the International System for Human Cytogenetic Nomenclature 2020 (ISCN-2020). While her husband’s karyotype was normal; the patient had a pericentric X chromosome inversion, described as 46,X,inv(X)(p11.2q26) (Figure 1, Figure 2). To perform a segregation analysis, a conventional cytogenetic investigation was performed on the parents, two brothers, and both offsprings of the patient. It was shown that the proband’s father and daughter were also carriers of the X chromosome inversion, and the other family members had normal karyotypes. No individual with a recombinant chromosome was observed in the family (Figure 3). Appropriate informed consent was obtained from the family members for sharing their and their children’s data.

INTRODUCTION

Chromosome inversions are abnormal structural rearrangements arising from double breaks on the same chromosome followed by the segment between these breakpoints reversed and reattached. According to the localization of the breakpoints, there are two types of inversions: paracentric and pericentric. In paracentric inversions, both breaks occur on the same chromosome arm. In contrast, in pericentric inversions, which are more commonly observed, breaks are on the different sides of the centromere. Therefore, the inverted fragment includes the centromere. Inversions including the pericentric heterochromatin region on chromosomes 1, 9, 16, and Y are commonly regarded as polymorphisms. Breakpoints in these inversions are believed to be located in non-coding areas or repeat regions, causing them to be clinically benign. On the other hand, inversions that arise de novo and affect euchromatic regions may have direct health implications (1).

Inversion of an autosomal chromosome is observed in approximately 1%-2% of the general population. The significance of the clinical outcome is expected to be correlated with the size of the inverted segment. However, X chromosome inversions are extremely rare, with an estimated incidence of 1/28,000-30,000 and their phenotypic implications are much more complicated (2).

Because of the conservation of the total genetic material, inversions are usually not associated with severe morphological effects; however, carriers may have reproduction issues, including infertility and recurrent pregnancy losses, because of gametes with an unbalanced karyotype. If one of the parents is known to be an inversion carrier, the risk of imbalanced gamete formation has been estimated as 5-10% and the risk of having offspring with malformations is around 1%. These risk ratios depend on the size of the inverted fragment. If the region distally located to the inversion is smaller, the clinical findings are expected to be less severe because of lower gene content (3). Here we describe a case with an X-chromosome pericentric inversion presenting with habitual abortus.