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Case Reports
. 2025 Jan 9;25(1):18.
doi: 10.1186/s12887-024-05267-z.

Long read Nanopore sequencing identifies precise breakpoints of a de novo paracentric inversion that disrupt the MEIS2 gene in a Chinese girl with syndromic developmental delay

Jianxin Tan #  1 , Mingtao Huang #  1 , Xiuqing Ji  1 , An Liu  1 , Fengchang Qiao  1 , Cuiping Zhang  1 , Lulu Meng  1 , Yan Wang  1 , Zhengfeng Xu  2 , Ping Hu  3
Affiliations
Case Reports

Long read Nanopore sequencing identifies precise breakpoints of a de novo paracentric inversion that disrupt the MEIS2 gene in a Chinese girl with syndromic developmental delay

Jianxin Tan et al. BMC Pediatr. .

Abstract

Background: Chromosomal inversions are underappreciated causes of rare diseases given their detection, resolution, and clinical interpretation remain challenging. Heterozygous mutations in the MEIS2 gene cause an autosomal dominant syndrome characterized by intellectual disability, cleft palate, congenital heart defect, and facial dysmorphism at variable severity and penetrance.

Case presentation: Herein, we report a Chinese girl with intellectual disability, developmental delay, and congenital heart defect, in whom G-banded karyotype analysis identified a de novo paracentric inversion 46,XX, inv(15)(q15q26.1) and other conventional approaches including chromosomal microarray analysis and whole exome sequencing were failed to detect any pathologic variants that can explain the phenotypes of the proband. Subsequently, long-read Nanopore sequencing was directly conducted and defined the breakpoint position of the inversion, disrupting the MEIS2 gene at intron 8. These breakpoints were also confirmed by Sanger sequencing.

Conclusions: In conclusion, we report the first chromosomal inversion disrupting the MEIS2 gene, which was fine-mapped by long read Nanopore sequencing. Our data not only expand the clinical spectrum of MEIS2-caused syndromic developmental delay, but also illustrate the value of long-read sequencing in elucidating the precise genetic etiology of patients with relatively nonspecific clinical findings and chromosomal inversion that are beyond the resolution of conventional approaches.

Keywords: Long read sequencing; MEIS2; Paracentric inversion; Syndromic developmental delay.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The written informed consent for the study was obtained from the parents of the proband, and all procedures were reviewed and approved by the Institutional Review Board of Nanjing Women and Children’s Healthcare Hospital (No. [2021] KY-104). Consent for publication: The written informed consent for publication was obtained from the parents of the proband. Clinical trial number: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Clinical characteristics of the proband. (A) Photograph of the proband. (B) Karyotype analysis revealed a de novo paracentric inversion 46,XX, inv (15)(q15q26.1) in the proband
Fig. 2
Fig. 2
Analysis of the proband by nanopore-based long-read sequencing. (A) SVs identified by nanopore-based long-read sequencing before and after filtering. (B) Flow diagram of the genetic strategies for the proband. (C) Integrative genomics viewer (IGV) visualization of alignments of the Nanopore reads from the whole genome sequence analysis of the proband for chromosome 15
Fig. 3
Fig. 3
Fine mapping of the paracentric inversion 46,XX, inv (15)(q15q26.1) by nanopore-based long-read sequencing. (A) Screenshot of the genomic regions containing 46,XX, inv (15)(q15q26.1). (B) The upper-left image indicates schematic representation for the paracentric inversion, in which a chromosomal segment is inverted in the opposite orientation. The red arrows denote the location of primers used for Sanger sequencing of breakpoints. The yellow arrow indicates the orientation of an un-inverted chromosome. In the upper-right image, the location of the paracentric inversion is highlighted in yellow. The below image denotes schematic diagram for the paracentric inversion. The black circles represent the breakpoints, and the yellow lines indicate the orientation of the paracentric inversion. (C) Sanger sequencing results for the PCR products including the breakpoints
See this image and copyright information in PMC

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