| 1q21.1 duplication syndrome | |
|---|---|
| Classification and external resources | |
| OMIM | 612475 |
1q21.1 duplication syndrome or 1q21.1 (recurrent) microduplication is a rare aberration of chromosome 1. Unique, the international rare chromosome disorder group, has 38 genetically confirmed registered cases of this duplication worldwide (november 2011).
In a common situation a human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 duplication syndrome one chromosome of the pair is over complete, because a part of the sequence of the chromosome is duplicated twice or more. In 1q21.1, the '1' stands for chromosome 1, the 'q' stands for the long arm of the chromosome and '21.1' stands for the part of the long arm in which the duplication is situated.
Next to the duplication syndrome, there is also a 1q21.1 deletion syndrome. While there are two or three copies of a similar part of the DNA on a particular spot with the duplication syndrome, there is a part of the DNA missing with the deletion syndrome on the same spot. Literature refers to both the deletion and the duplication as the 1q21.1 copy-number variations (CNV).
The CNV leads to a very variable phenotype and the manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way, while others have symptoms of mental retardation and various physical anomalies.
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The structure of 1q21.1 is complex. The area has a size of approximately 6 Megabase (Mb) (from 141.5 Mb to 147.9 Mb). Within 1q21.1 there are two areas where a duplication or deletion can be found: the TAR-area for the TAR syndrome and the distal area for other anomalies. The 1q21.1 duplication syndrome will commonly be found in the distal area, but an overlap with the TAR-area is possible. 1q21.1 has multiple repetitions of the same structure (areas with the same color in the picture have equal structures) Only 25% of the structure is unique. There are several gaps in the sequence. There is no further information available about the DNA-sequence in those areas up till now. The gaps represent approximately 700 Kilobase. New genes are expected in the gaps. Because the gaps are still a topic of research, it is hard to find the exact start and end markers of a deletion. The area of 1q21.1 is one of the most difficult parts of the human genome to map.
Recognised symptoms up till now are:
It is not clear whether the list of symptoms is complete. Very little information is known about the syndrome. The symptomology may be different among individuals, even in the same family.
Genes related to 1q21.1 deletion in the TAR area are HFE2, TXNIP, POLR3GL, LIX1L, RBM8A, PEX11B, ITGA10, ANKRD35, PIAS3, NUDT17, POLR3C, RNF115, CD160, PDZK1, and GPR89A
Genes related to 1q21.1 deletion in the distal area are HYDIN2, PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, and GPR89B.
The syndrome may appear in cases where neither of the parents carries the genes. Because of the repetitions in 1q21.1, there is a larger chance on an unequal crossing-over during meiosis. In this situation, parts of the chromosome may get lost. Accidental changes appear in the chromosome. In the situation of an unequal crossing-over, copy-number variation (CNVs) will appear. These CNVs will lead to deletions or duplications. About 0.4% of the human genome has CNVs, and it is a common process. Such an accidental mutation is called a 'de novo'-situation, and it appears 75% of the cases.
In 25% of the cases, one of the parents is an unaffected carrier of the syndrome. Sometimes adults have mild problems with the syndrome. To find out whether either of the parents carries the syndrome, both parents have to be tested.
In several cases, the syndrome is detected in adults only after their child is diagnosed. Sometimes the symptoms are mild enough that a person can go decades without receiving a diagnosis.
In families where both parents have been tested negative on the syndrome, chances of a second child with the syndrome are extremely low. If the syndrome was found in the family, chances on a second child with the syndrome are 50%. The effect of the syndrome on the child cannot be predicted.
For parents who have a child with the syndrome, it is advisable to consult a physician before a next pregnancy and to do prenatal screening.
Several researchers around the world are studying on the subject of 1q21.1 duplication syndrome. The syndrome was identified for the first time in people with heart abnormalities. The syndrome was later observed in patients who had autism or schizophrenia.
1q21.1 duplication syndrome supports a possible link between autism and schizophrenia. Both autism and schizophrenia have been linked to some of the same genes; while both are distinct disorders, there appears to be some overlap in the affected genes.[1]
In the genetic area, relations have been found between both autism and schizophrenia based on duplications and deletions of chromosomes. Statiscal research showed that schizophrenia is significantly more common in combination with 1q21.1 deletion syndrome. On the other side, autism is significantly more common with 1q21.1 duplication syndrome. Similar observations were done for chromosome 16 on 16p11.2 (deletion: autism/duplication: schizofrenia), chromosome 22 on 22q11.21 (deletion (Velo-cardio-facial syndrome): schizophrenia/duplication: autism) and 22q13.3 (deletion (Phelan-McDermid syndrome): schizofrenia/duplication: autism). Research on autism/schizophrenia relations for chromosome 15 (15q13.3), chromosome 16 (16p13.1), and chromosome 17 (17p12) on the subject of deletions/duplications are still inconclusive.
Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.[2]
Research is done on 10-12 genes on 1q21.1 that produce DUF1220-locations. DUF1220 is an unknown protein, which is active in the neurons of the brain near the neocortex. Based on research on apes and other mammals, it is assumed that DUF1220 is related to cognitive development (man: 212 locations; chimpanzee: 37 locations; monkey: 30 locations; mouse: 1 location). It appears that the DUF1220-locations on 1q21.1 are in areas that are related to the size and the development of the brain. The aspect of the size and development of the brain is related to autism (macrocephaly) and schizophrenia (microcephaly). It is assumed that a deletion or a duplication of a gene that produces DUF1220-areas might cause growth and development disorders in the brain [3]
Another relation between macrocephaly with duplications and microcephaly with deletions has been seen in research on the HYDIN Paralog or HYDIN2. This part of 1q21.1 is involved in the development of the brain. It is assumed to be a dosage-sensitive gene. When this gene is not available in the 1q21.1 area it leads to microcephaly. The HYDIN2 is a copy of the HYDIN found on 16q22.2.