De Novo Complex Genomic Rearrangement Spanning 2q31.1 in a Proband With Congenital Malformations: Genotype-Phenotype Correlation and Development of a CGR Detection Pipeline

Authors

• Katherine Helle
• Jesse D Bengtsson
• Mira Gandhi
• Christopher M Grochowski
• Ming Yin Lun
• Neha Sudhir
• Shalini N Jhangiani
• Fritz J Sedlazeck
• Seema R Lalani
• Neil A Hanchard
• Claudia M B Carvalho

Language

English

Publication Date

8-1-2026

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.70153

PMID

41943674

PMCID

PMC13285943

PubMedCentral® Posted Date

6-23-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house CGR pipeline detected five additional rearrangements throughout the genome confirmed by orthogonal methodologies as inherited and unlikely to impact this individual's phenotype. Importantly, these catastrophic genomic events, chromoanasynthesis-like, are surprisingly commonly observed in the genome, inherited and involve large regions of the genome. Moreover, such inherited CGRs often include copy-number gains that partially affect disease-causing genes which complicate clinical interpretation. Overall, we show the utility of short-read sequencing to uncover de novo and inherited chromoanasynthesis events and established genotype-phenotype correlation in a proband with multiple congenital malformations.

Keywords

Humans, Genetic Association Studies, Chromosomes, Human, Pair 2, Abnormalities, Multiple, Gene Rearrangement, Congenital Abnormalities, DNA Copy Number Variations, Phenotype, Male, Tetralogy of Fallot, Female, chromothripsis, copy-number variants, dosage effects, genomic disorders, long-read sequencing, PacBio HiFi, rare genetic diseases, structural variants

Published Open-Access

yes

Recommended Citation

Helle, Katherine; Bengtsson, Jesse D; Gandhi, Mira; et al., "De Novo Complex Genomic Rearrangement Spanning 2q31.1 in a Proband With Congenital Malformations: Genotype-Phenotype Correlation and Development of a CGR Detection Pipeline" (2026). Faculty, Staff and Students Publications. 7168.
https://digitalcommons.library.tmc.edu/baylor_docs/7168