BACKGROUND: Distinguishing paracentric inversions (PAIs) from chromosomal insertions has traditionally relied on fluorescent in situ hybridization (FISH) techniques, but recent advancements in high-throughput sequencing have enabled the use of genome sequencing for such differentiation. In this study, we present a 38-year-old male carrier of a paracentric inversion on chromosome 2q, inv (2)(q31.2q34), whose partner experienced recurrent miscarriages.
METHODS: FISH analysis confirmed the inversion, and genome sequencing was employed for detailed characterization.
RESULTS: Preimplantation genetic testing (PGT) revealed that all assessed embryos were balanced, consistent with the low risk of unbalanced offspring associated with PAIs. While PAI carriers traditionally exhibit low risk of producing unbalanced offspring, exceptions exist due to crossover events within the inversion loop. Although the sample size was limited, the findings align with existing sperm study data, supporting the rare occurrence of unbalanced progeny in PAI carriers.
CONCLUSIONS: This study highlights the possibility of characterizing PAIs using genome sequencing to enable correct reproductive counseling and PGT decisions. Detailed characterization of a PAI is crucial for understanding potential outcomes and guiding PGT strategies, as accurate knowledge of the inversion size is essential for appropriate method selection in PGT. Given the very low risk of unbalanced offspring in PAI carriers, routine PGT may not be warranted but should be considered in specific cases with a history of unbalanced progeny or recurrent miscarriages. This study contributes to our understanding of PAI segregation and its implications for reproductive outcomes.

UNASSIGNED: Chromosomal abnormalities are mostly found in 0.5-0.8% of live-born infants with developmental and morphological defects. Paracentric inversions are structural intrachromosomal rearrangements resulting in a risk of chromosomally unbalanced gametes in carriers.
UNASSIGNED: Herein, we report a patient with dicentric rearrangement of chromosome 18 due to maternal paracentric inversion of chromosome 18. The patient was a girl, aged 3 years and 11 months. She was referred due to multiple congenital abnormalities, severe intellectual disability, and motor retardation. She had microcephaly, prominent metopic suture, synophrys, epicanthic folds, telecanthus, wide-set alae nasi, wide columella, bilateral cleft lip and palate, pectus carinatum, umbilical hernia, pes planus, and anteriorly displaced anus. She had bilateral external auditory canal stenosis and mild right-sided and moderate left-sided sensorineural hearing loss. Echocardiography showed secundum-type atrial septal defect and mild tricuspid failure. Brain magnetic resonance imaging showed only thinning of posterior areas of the corpus callosum. Chromosome analysis showed 46,XX,dic rec(18) by GTG and C banding. Dicentric chromosome was confirmed by fluorescence in situ hybridization analysis. Paternal karyotype was normal 46,XY but maternal chromosome analysis showed a paracentric inversion in chromosome 18 with 46,XX,inv(18)(q11.2?q21.3?) karyotype. Array CGH was performed on a peripheral blood sample from the patient and showed duplication at 18p11.32p11.21 and 18q11.1q11.2, and deletion at 18q21.33q23. The patient\'s final karyotype is arr 18p11.32p11.21(64,847_15,102,598)×3,18q11.1q11.2(18,542,074_22,666,470)×3,18q21.33q23(59,784,364_78,010,032)×1.
UNASSIGNED: To the best of our knowledge, this is the first report of a patient with dicentric chromosome 18 due to a parental paracentric inversion of chromosome 18. We present the genotype-phenotype correlation with literature review.

Detection and precise genomic mapping of balanced chromosomal abnormalities in patients with impaired fertility or a clinical phenotype represent a challenge for current cytogenomics owing to difficulties with precise breakpoint localization in the regions enriched for DNA repeats and high genomic variation in such regions. Here, we present a comprehensive cytogenomic approach to breakpoint mapping in a rare paracentric inversion on 10q (in a patient with oligoasthenoteratozoospermia and necrozoospermia) that does not affect other phenotype traits. Multicolor banding, chromosomal microarray analysis, chromosome microdissection with reverse painting, and single-copy sequencing of the rearranged chromosome were performed to determine the length and position of the inverted region as well as to rule out a genetic imbalance at the breakpoints. As a result, a paracentric 19.251 Mbp inversion at 10q22.2q23.3 was described. The most probable location of the breakpoints was predicted using the hg38 assembly. The problems of genetic counseling associated with enrichment for repeats and high DNA variability of usual breakpoint regions were discussed. Possible approaches for cytogenomic assessment of couples with balanced chromosome rearrangements and problems like reproductive failures were considered and suggested as useful part of effective genetic counseling.

The genus Mazama stands out among the Neotropical deer due to their wide intra and interspecific karyotypic diversification, which is associated with an accentuated chromosomal fragility. There are reports of heterozygous Robertsonian translocation (RT) carriers in a free-range population of Mazama gouazoubira (brown brocket deer), as well as in captive animals of this and other species of the genus. To analyze possible negative impacts of heterozygous chromosome rearrangements on reproductive fitness of the carriers, we performed an analysis of sperm meiotic segregation in four brown brocket bucks, carriers of a rob(4;16), and compared the results with those of a normal buck. We established a reliable FISH and sperm-FISH protocol for the brown brocket deer using bovine (Bos taurus; diploid number, 2n = 60) whole chromosome painting (WCP) and BAC probes. Using BAC probes, we revealed the presence of a paracentric inversion (PAI) of the fused chromosome 4 in two of the four analyzed RT carriers. The mean frequency of normal/balanced sperm in the translocation carriers was significantly lower than in the normal buck (94.78% vs 98.40%). The mean value of total unbalanced spermatozoa was almost doubled in the RT/PAI carriers (6.68%) when compared to RT carriers (3.76%), but the difference was not statistically significant. This study demonstrated the efficiency of FISH with bovine WCP and BAC probes in the characterization of chromosome rearrangements and gametic segregation patterns in brown brocket deer. Our results indicate a low to moderate increase in the rates of unbalanced meiotic segregation products in brown brocket bucks heterozygous for RT and RT/PAIs.

Usher type 1 syndrome is a rare autosomal recessive disorder involving congenital severe-to-profound hearing loss, development of vision impairment in the first decade, and severe balance difficulties. The PCDH15 gene, one of the five genes implicated in this disease, is involved in 8-20% of cases. In this study, we aimed to identify and characterize the two causal variants in a French patient with typical Usher syndrome clinical features. Massively parallel sequencing-based gene panel and screening for large rearrangements were used, which detected a single multi-exon deletion in the PCDH15 gene. As the second pathogenic event was likely localized in the unscreened regions of the gene, PCDH15 transcripts from cultured nasal cells were analyzed and revealed a loss of junction between exon 13 and exon 14. This aberration could be explained by the identification of two fusion transcripts, PCDH15-LINC00844 and BICC1-PCDH15, originating from a 4.6 Mb inversion. This complex chromosomal rearrangement could not be detected by our diagnostic approach but was instead characterized by long-read sequencing, which offers the possibility of detecting balanced structural variants (SVs). This finding extends our knowledge of the mutational spectrum of the PCDH15 gene with the first ever identification of a large causal paracentric inversion of chromosome 10 and illustrates the utility of screening balanced SVs in an exhaustive molecular diagnostic approach.

Apparently, balanced chromosomal rearrangements usually have no phenotypic consequences for the carrier. However, in some cases, they may be associated with an abnormal phenotype. We report herein the case of a 4-year-old boy presenting with clinically isolated supravalvular aortic stenosis (SVAS). No chromosomal imbalance was detected by array CGH. The karyotype showed a balanced paracentric chromosome 7 inversion. Breakpoint characterization using paired-end whole-genome sequencing (WGS) revealed an ELN gene disruption in intron 1, accounting for the phenotype. Family study showed that the inversion was inherited, with incomplete penetrance. To our knowledge, this is the first case of a disruption of the ELN gene characterized by WGS. It contributes to refine the genotype-phenotype correlation in ELN disruption. Although this disruption is a rare etiology of SVAS, it cannot be detected by the diagnostic tests usually performed, such as array CGH or sequencing methods (Sanger, panel, or exome sequencing). With the future perspective of WGS as a diagnostic tool, it will be important to include a structural variation analysis in order to detect balanced rearrangements and gene disruption.

OBJECTIVE: Xp11 rearrangement in renal cell carcinoma (RCC) typically involves gene fusion to the gene encoding transcription factor E3 (TFE3), a member of the microphthalmia-associated transcription factor family on chromosome Xp11.2. Dual-colour break-apart fluorescence in-situ hybridisation (FISH) is recommended to confirm histological diagnoses. Recently, RNA-binding motif protein 10 (RBM10), encoded by a gene on chromosome Xp11.3, was identified as a chimeric partner of TFE3; thus, RBM10-TFE3 fusion results from paracentric inversion. RBM10-TFE3 RCC may yield a false-negative result in FISH analysis of TFE3 expression. The aim of the present study was to investigate the clinicopathological features of RBM10-TFE3 RCC.
RESULTS: Ten patients with RBM10-TFE3 RCC aged 31-71 years were investigated. Histological analysis, immunostaining, dual-colour break-apart FISH for TFE3, reverse transcription polymerase chain reaction and sequencing analysis were performed. No patient had a history of exposure to chemotherapy. Two of these patients died of RCC, and three were alive but developed metastases. Microscopically, the tumours were composed of a mixed architecture of tubulocystic and papillary patterns with scattered psammoma bodies. The tumours showed strong nuclear immunoreactivity for TFE3. FISH showed consistent closely spaced split signals in the RCCs of four patients, and polysomic signals with occasional closely spaced split signals in the RCCs of six patients. Of the latter six patients, five had renal failure, and four developed tumours in kidneys subjected to haemodialysis.
CONCLUSIONS: The present study suggests that the carcinogenesis of RBM10-TFE3 RCC in some, but not all, patients may be associated with chronic kidney disease. The aggressive nature of RBM10-TFE3 RCC should be considered, as five patients experienced metastases.

Partial trisomies have often been reported secondary to inversion mutations. These occurrences are most frequently associated with pericentric inversions. In this report, we describe the first documented case of partial trisomy 13 secondary to a parental paracentric inversion, in this case a paternal paracentric 13q inversion. Our Patient exhibits a variety of clinical findings including global developmental delay with intellectual disability, sensorineural hearing loss, bilateral congenital polar cataracts with associated foveal and optic nerve hypoplasia, right retinal detachment, atrial septal defect, absence of corpus callosum, celiac disease, microcephaly, as well as other dysmorphic features.