Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism

Dong Li; Alanna Strong; Cuiping Hou; Helen Downes; Amanda Barone Pritchard; Pamela Mazzeo; Elaine H Zackai; Laura K Conlin; Hakon Hakonarson

doi:10.1186/s13039-022-00610-4

Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism

Mol Cytogenet. 2022 Aug 5;15(1):33. doi: 10.1186/s13039-022-00610-4.

Authors

Dong Li^#^{1

2

3}, Alanna Strong^#^{4

5

6}, Cuiping Hou⁴, Helen Downes⁴, Amanda Barone Pritchard⁷, Pamela Mazzeo⁸, Elaine H Zackai^{5

6}, Laura K Conlin^{9

10}, Hakon Hakonarson^{4

5

6}

Affiliations

¹ Center for Applied Genomics, The Children's Hospital of Philadelphia, Abramson Research Building, Suite 1016I, 3615 Civic Center Boulevard, Philadelphia, PA, 19104-4318, USA. [email protected].
² Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. [email protected].
³ Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
⁴ Center for Applied Genomics, The Children's Hospital of Philadelphia, Abramson Research Building, Suite 1016I, 3615 Civic Center Boulevard, Philadelphia, PA, 19104-4318, USA.
⁵ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, University of Michigan Health, Ann Arbor, MI, USA.
⁸ Division of General Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁹ Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

^# Contributed equally.

Abstract

Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.