Chromosome 1q21.1 duplication is observed in 0.03% of the general population. Patients with Tetralogy of Fallot or schizophrenia are 15-21 times more likely to have this chromosomal duplication. Tetralogy of Fallot is a rare condition caused by a combination of four heart defects present at birth.

Chromosome 1q21.1 duplication syndrome occurs when a segment of one copy of chromosome 1 is abnormally copied at region q21.1 There is some evidence that the duplication occurs as a result of a process known as nonallelic homologous recombination. Each human cell contains 23 pairs of chromosome except reproductive cells. When cells divide to produce reproductive cells, pairs are split and each new reproductive cell receives 23 individual chromosomes. During this division, another process called homologous recombination occurs where segments of one chromosome move to the other chromosome in that pair. This process sometimes leads to spontaneous changes in DNA structure such as a duplication or deletion. The duplication can be inherited from a parent with chromosome 1q21.1 duplication or can occur when the reproductive cells are produced before the individual is conceived in which case; the parents are unaffected.

The 1q21.1 region contains at least 12 genes including PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, GPR89B. CHD1L and PRKAB2 which encode a protein responsible for DNA repair and a protein for fat metabolism respectively, are suggested to contribute to epilepsy. GJA5 and GJA8 encode two gap junction proteins, which provide a route between adjacent cells for transport of small molecules. Duplication of these genes is likely to contribute to congenital heart defects. However, current information on the association between specific duplicated genes and clinical presentations are very inconclusive. FMO5 and ACP6 encode for two enzymes, which are proteins that allow biological reactions to occur at a faster rate. When cells reproduce, they must replicate their genetic content to pass on to the newly formed cell. CHD1L encodes for a protein involved in DNA replication. BCL9 encodes for a protein that controls and regulates other genes. Finally, GPR89B encodes for a protein that controls how acidic or basic the environment of the Golgi apparatus is. The Golgi apparatus is a cell compartment that performs a specific function within the cell.

Affected individuals may have developmental and intellectual disabilities. Features of autism spectrum disorder are commonly observed in affected individuals. These features include impaired communication and socialization skills. Delayed language and speech development are also common where vocabulary and production of speech tend to be more impaired than the ability to understand speech. Although, there have been rare reports on individuals affected by chromosome 1q21.1 duplication with high verbal skills and borderline cognitive performance. A higher risk of attention deficit hyperactivity disorder is also observed in affected children. Schizophrenia, anxiety, and depression may also be present. In some affected individuals, heart abnormalities may occur, particularly tetralogy of Fallot which involves a combination of four different heart defects. Rare cases of epilepsy have also been reported.  Chromosome 1q21.1 is also associated with abnormal head size and slightly abnormal facial features.

Many affected individuals are not diagnosed as symptoms are common to many other disorders. Some affected individuals may be too young to present common symptoms at the time of examination. The onset of common symptoms varies.

Diagnosis can be established through genetic testing.

Chromosome 1q21.1 duplication is a syndrome associated with copy number variation. Copy number is the number of copies of a specific gene in a chromosome. Although there are variations in copy number among healthy individuals for specific genes, this variation is sometimes associated with a disorder. Copy number variation is commonly detected using array comparative genomic hybridization (aCGH) profiling. In this method, the suspected sample is compared to a known normal genome (a complete set of genes present in a cell), to identify regions of copy number variation. Additionally, next-generation sequencing (NGS) has been recently used to identify smaller copy number variation. Nucleotides are the building blocks of DNA and chromosomes. It is the specific sequence of nucleotides that determines the function of a gene. NGS is a technique that determines the exact sequence of the nucleotides in a region of a chromosome and can be used to detect copy number variation.

The severity and type of symptoms in chromosome 1q21.1 duplication syndrome vary among affected individuals significantly. Treatment is often targetted at specific symptoms present in each affected individual and is multifactorial.

Genetic Home Reference. 1q21.1 microduplication. 2018. Available from https://ghr.nlm.nih.gov/condition/1q211-microduplication#inheritance

Haldeman-Englert CR, Jewett T. 1q21.1 Recurrent Microdeletion. 2011 Feb 24 [Updated 2015 Nov 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet].

Brunetti-Pierri N, et al. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics. 2008;40:1466–1471. Available from https://www.nature.com/articles/ng.279

Xavier J et al. 1q21.1 microduplication: large verbal–nonverbal performance discrepancy and ddPCR assays of HYDIN/HYDIN2 copy number. Nature. 2018;24(3). Available from https://www.nature.com/articles/s41525-018-0059-2

Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK52787/

Mefford H, et al. Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes. The New England Journal of Medicine. 2008;359:1685-1699. DOI: 10.1056/NEJMoa0805384

Dolcetti A et al. 1q21.1 Microduplication expression in adults. Genetics in medicine: official journal of the American College of Medical Genetics. 2012;15(4): 282-9.

Gourari I, Schubert R, Prasad A.1q21.1 Duplication syndrome and epilepsy. Neurology Genetics. 2018; 4(1):219; DOI: 10.1212/NXG.0000000000000219

Brunetti-Pierri, Nicola et al. “Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities” Nature genetics vol. 40,12 (2008): 1466-71.

Soemedi R, Topf A, Wilson IJ, et al. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls. Hum Mol Genet. 2011;21(7):1513-20.

Busè M, Cuttaia HC, Palazzo D, et al. Expanding the phenotype of reciprocal 1q21.1 deletions and duplications: a case series. Ital J Pediatr. 2017;43(1):61. Published 2017 Jul 19. doi:10.1186/s13052-017-0380-x

Gourari I, Schubert R, Prasad A. 1q21.1 Duplication syndrome and epilepsy: Case report and review. Neurol Genet. 2018;4(1):e219. Published 2018 Jan 18. doi:10.1212/NXG.0000000000000219

Hayes J, et al. Diagnosis of copy number variation by Illumina next-generation sequencing is comparable in performance to oligonucleotide array comparative genomic hybridization. Genomics. 2013;102(3):174-83. DOI: 10.1016/j.ygeno.2013.04.006

Ellingford JM, Campbell C, Barton S, et al. Validation of copy number variation analysis for next-generation sequencing diagnostics. Eur J Hum Genet. 2017;25(6):719-724.