Balanced chromosomal insertions microstructural abnormalities

Chromosomal insertions often cause structural abnormalities that result in an overt phenotype and symptoms. However, those who carry balanced insertions can be asymptomatic when disease-causing genes are not disrupted. While the individual may not be affected, the balanced insertion could serve as an underlying mechanism for recurrent familial microstructural abnormalities and copy number variants (CNVs) when meiosis produces unbalanced gametes. This can result in miscarriage or congenital defects.

Shirai et al. examines two families with chromosomal microstructural abnormalities involving the same regions over several generations. In family A, the proband is a 4-year-old girl with developmental delay and tonic seizures. The asymptomatic parents had a second child who was also asymptomatic at age 3. Cytogenetic examination of the probing revealed microduplication of 13q31.2-q33. This abnormality occurred due to insertion of the 13q31.2-q33 segment into chromosome 10 in one of the parents. During the third pregnancy, prenatal examination of the fetus showed a reciprocal microdeletion of 13q, resulting in the decision to terminate. This region contains the NACLN gene involved in sodium channel activity and neuronal excitability which may explain the neurological phenotype in the proband. Using long-read whole-genome sequencing (WGS) and breakpoint analysis, the authors identified the parent carrying the structural abnormality involving the 13q segment. This segment split into two and was inserted into 10q25.2 without disturbing any disease-causing genes. In the affected offspring (both the proband and terminated pregnancy), meiotic segregation allowed the transmission of the affected chromosomes to result in microduplication and reciprocal microdeletion. Genetic analysis further revealed that the breakpoint-junctions in the parent mirrored those in the proband.

In family B, the proband is a 39-year-old female displaying psychomotor delay, hypotonia, and a cleft lip.

Although the parents showed no symptoms, her family history revealed intellectual disability on the paternal side. Fluorescence in situ hybridization (FISH) testing originally suggested a de novo 1p36 microdeletion due to the inability to detect the abnormality in either parent. However, the proband’s cousin displayed epilepsy, developmental delay, and dysmorphic facial features that prompted chromosomal microarray (CMA) to be performed. This revealed a 1p36 deletion, suggesting a previously overlooked familial microstructural abnormality on chromosome 1. Upon further analysis, long-read WGS and breakpoint analysis confirmed an intrachromosomal insertion in the father, involving 1p36.33-p36.31 into 1p36.13. Shirai et al.’s study of these two families demonstrate the importance of considering balanced chromosomal insertions as underlying causes of familial CNVs, even in cases where CNVs are initially believed to be de novo. Furthermore, these variants may be too complex to be detected with routine laboratory tests such as FISH and may require long-read sequencing to uncover structural abnormalities.

Shirai et al. “Balanced chromosomal insertions as the mechanism of recurrent familial microstructural abnormalities: detailed analyses using long-read whole-genome sequencing” . “Journal of Human Genetics” 2025, In press.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. Review and formatting by Jaden Miller. For more information on any article please contact info@chromodisorder.org