Low-Level Chromosomal Mosaicism in Neurodevelopmental Disorders

Abstract

Chromosomal mosaicism, which represents a diagnostic challenge for detection and interpretation, has been described in several genetic conditions. It can contribute to a large phenotypic variation in diseases. At analysis of a well-characterized cohort of 714 patients with neurodevelopmental disorders (NDDs) of unknown etiology using a high-resolution chromosomal microarray platform, we found 2 cases (0.28%) of low-level mosaicism and defined a previously detected extra chromosome in a third patient. Two of the cases were mosaics for segmental imbalances (a partial trisomy 3q26.1q27.3 and a partial monosomy 18q21.2qter with 14.6 and 20% mosaic ratios in lymphocytes, respectively), and 1 was a mosaic for an entire chromosome (trisomy 14, mosaic ratio 20%). Our diagnostic yield is in line with the ratios previously published in patients with intellectual disability. Notably, the partial trisomy 3q26.1q27.3 case is an example of a rare and unusual class of a rearranged neocentric ring chromosome, which can neither be categorized in class I, nor in class II of such rearrangements. Our cases further elucidate the phenotypes related to the aberrations of the specific chromosome segments observed and underline the important role of low-level mosaics in the pathogenesis of NDDs of unknown etiology even in the absence of clinical signs of mosaicism.

Keywords: Deletion 18q; Microarray; Mosaicism; Neocentromere; Neurodevelopmental disorders.

Fig. 1

Mosaic duplication of 3q26.1q27.3 in a patient with mild intellectual disability and postaxial polydactyly of the hands. A G-banding of the 2 normal chromosomes 3 and the neocentric ring chromosome. B Screenshot of microarray raw data. The arrowhead indicates the smooth signal of markers, indicative of the interstitial mosaic duplication in 3q26.1q27.3, slightly above 2. Chromosomal position and cytobands are given at the bottom. CMA copy number state: 2.3.

Fig. 2

Mosaic deletion of 18q21.2qter in a patient with developmental delay and atresia of auditory canal. A Photograph of the patient at the age of 2½ years. Note the broad forehead, hypertelorism, flat nasal root, epicanthal folds, upturned nares, and everted lips. B Screenshot of microarray raw data. The arrowhead indicates the smooth signal of markers, indicative of the mosaic terminal on chromosome 18, slightly below 2. Chromosomal position and cytobands are given at the bottom. CMA copy number state: 1.7.