Complex and Dynamic Chromosomal Rearrangements in a Family With Seemingly Non-Mendelian Inheritance of...

Area of Science:

• Genetics
• Neurology
• Genomic Medicine

Background:

• Chromosomal rearrangements are increasingly recognized as causes of neurologic disorders, often presenting with phenotypes beyond typical gene-specific spectra.
• Complex genetic variations can lead to unusual inheritance patterns, challenging traditional genetic diagnosis.

Purpose of the Study:

• To identify the causal genetic variant in a large US family exhibiting co-occurring dopa-responsive dystonia (DRD) and skeletal/eye abnormalities.
• To understand the mechanism behind a seemingly non-Mendelian inheritance pattern in this family.

Main Methods:

• Examined 10 family members using fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and whole-genome sequencing.
• Investigated genomic variations, including large deletions and complex chromosomal rearrangements.

Main Results:

• Identified a large heterozygous deletion of all 6 exons of the GCH1 gene in 5 affected individuals, correlating with DRD.
• Observed co-occurring skeletal and eye abnormalities (ptosis, myopia, retinal detachment) in mutation carriers.
• Discovered complex chromosomal rearrangements on chromosome 14q21-22 that expanded into larger deletions, explaining the non-Mendelian inheritance and implicating BMP4 in digital/eye abnormalities.

Conclusions:

• Clinical red flags, such as the unexpected co-occurrence of DRD with skeletal and eye issues, should prompt investigation for chromosomal rearrangements.
• Accurate diagnosis and management of patients with such complex genetic disorders necessitate an interdisciplinary approach.