Low-Level Chromosomal Mosaicism in Neurodevelopmental Disorders.

Area of Science:

• Genetics
• Developmental Biology
• Clinical Diagnostics

Background:

• Chromosomal mosaicism, the presence of two or more cell populations with different karyotypes, complicates genetic diagnostics and contributes to phenotypic variability in genetic disorders.
• Detecting low-level mosaicism is crucial for understanding the genetic underpinnings of neurodevelopmental disorders (NDDs) of unknown etiology.

Purpose of the Study:

• To investigate the prevalence and diagnostic significance of low-level chromosomal mosaicism in a cohort of patients with neurodevelopmental disorders (NDDs) of unknown origin.
• To characterize the specific chromosomal aberrations and associated phenotypes in identified cases of mosaicism.

Main Methods:

• Analysis of a well-characterized cohort of 714 patients with NDDs using a high-resolution chromosomal microarray platform.
• Identification and characterization of chromosomal imbalances, including segmental and whole chromosome aneuploidies, with assessment of mosaic ratios in lymphocytes.

Main Results:

• Two cases (0.28%) of low-level mosaicism were detected, involving segmental imbalances (partial trisomy 3q and partial monosomy 18q) and one case of whole chromosome mosaicism (trisomy 14).
• One case presented a rare rearranged neocentric ring chromosome (partial trisomy 3q26.1q27.3), not fitting established classification systems.
• The diagnostic yield aligns with previously reported rates for intellectual disability cohorts.

Conclusions:

• Low-level chromosomal mosaicism plays a significant role in the pathogenesis of NDDs, even when not clinically apparent.
• The findings underscore the importance of sensitive detection methods for mosaicism in unexplained NDDs.
• Further elucidation of phenotypes associated with specific chromosomal segment aberrations is warranted.