Phenotypic Variability Associated with a Large Recurrent 1q21.1 Microduplication in a Three-Generation Family

Abstract

Recurrent copy number variants of the q21.1 region of chromosome 1 have been associated with variable clinical features, including developmental delay, mild to moderate intellectual disability, psychiatric and behavioral problems, congenital heart malformations, and craniofacial abnormalities. A subset of individuals is clinically unaffected. We describe a unique 3-generation family with a large recurrent 1q21.1 microduplication (BP2-BP4). Our observations underline the incomplete penetrance and phenotypic variability of this rearrangement. We also confirm the association with congenital heart malformations, chronic depression, and anxiety. Furthermore, we report a broader range of dysmorphic features. The extreme phenotypic heterogeneity observed in this family suggests that additional factors modify the clinical phenotype.

Keywords: 1q21.1 microduplication; Congenital heart defects; Copy number variation; GJA5.

Fig. 1

Pedigree of the family with a recurrent 1q21.1 microduplication (BP2-BP4). Squares indicate males, circles indicate females. Diamonds reflect persons of unspecified gender. An arrow points to the proband. Age of death (d.) is displayed below the symbol, and TOP indicates termination of pregnancy. The presence (+) or absence (-) of the 1q21.1 microduplication is indicated in the upper right corner.

Fig. 2

Facial features of family members carrying the 1q21.1 microduplication. a Patient IV-1 (proband). b Patient III-2 (mother of the proband). c Patient III-1. d Patient III-3. e Patient III-4. f Patient III-5. g Patient III-7. h Patient IV-4.

Fig. 3

a Facial features of the fetus (patient V-1). b Longitudinal section through the right ventricle showing a thickened and hypertrabeculated myocardium, the absence of a pulmonary valve, and tricuspid valve dysplasia with nodular thickening of the chordae tendineae (enlarged detail).