Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review.

Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long-term follow-up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.

Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.