Clinical and Molecular Spectrum of 1q21.1 Copy Number Variations: A Case Series

Background: 1q21.1 copy number variations (CNVs) are recurrent rearrangements with a clinical spectrum, from neurodevelopmental disorders and congenital anomalies to apparently unaffected carrier status, reflecting incomplete penetrance and variable expressivity. Methods: Our chromosomal microarray (CytoScan HD) database was retrospectively screened for pathogenic or likely pathogenic 1q21.1 CNVs. Results: Twenty probands from 19 families (14 postnatal, 6 prenatal) carried 21 CNV events: 11 deletions (52.4%) and 10 duplications (47.6%). Of these, 16 (76.2%) were confined to the distal segment, 3 (14.3%) to the proximal segment, and 2 (9.5%) spanned both. One proband carried coexisting proximal duplication and distal deletion, both inherited from an apparently unaffected father. Of the 17 probands (85%) with parental testing, 7 (41.2%) had de novo and 10 (58.8%) inherited CNVs. Distal CNVs were mostly observed in probands with neurodevelopmental or cardiac phenotypes, whereas bilateral upper extremity anomalies were observed in both prenatally ascertained fetuses with isolated proximal deletions. Corpus callosum atrophy and choanal atresia were infrequently reported co-occurring findings, whereas prenatal intracranial hemorrhage was potentially novel; each occurred in one proband. Given the small proximal subgroup and differing ascertainment, these segment-associated trends are descriptive. Conclusions: This series highlights the relevance of segment localization and parental segregation data in interpreting 1q21.1 CNVs.