1q21.1 duplication syndrome
Encyclopedia
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 more than complete, because a part of the sequence of the chromosome is repeated two or three times.
The main symptoms are mental retardation and various physical anomalies. The manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way.
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 a similar spot.
and the distal area for other anomalies. The area 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.
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.
, 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
.
. 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.
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.
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.
Research is done on 10-12 genes on 1q21.1 that produce DUF1220
-locations. DUF1220 is an unknown protein
, which is active in the neuron
s 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
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.
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 more than complete, because a part of the sequence of the chromosome is repeated two or three times.
The main symptoms are mental retardation and various physical anomalies. The manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way.
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
1q21.1 deletion syndrome
1q21.1 deletion syndrome or 1q21.1 microdeletion is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 48 genetically confirmed registered cases of this deletion worldwide ....
. 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 a similar spot.
The structure of 1q21.1
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). There are two areas where the duplication can be: the TAR-area for the TAR syndromeTAR syndrome
TAR Syndrome is a rare genetic disorder that is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count...
and the distal area for other anomalies. The area 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.
Symptoms
Recognised symptoms up till now are:- AutismAutismAutism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
or autistic behaviors - ADHD
- Learning disability
- Large head
- Dysmorphic facial appearance - mild
- Prominent forehead
- Wide-set eyes (hypertelorismHypertelorismHypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits . In this condition the distance between the inner eye corners as well as the distance between the pupils is greater than normal...
) - SchizophreniaSchizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
- Underdeveloped parts of brain - corpus callosum and cerebellar vermis
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.
Related genes
Genes related to 1q21.1 deletion in the TAR area are HFE2Hemojuvelin
Hemojuvelin is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene...
, TXNIP
TXNIP
Thioredoxin-interacting protein is a protein that in humans is encoded by the TXNIP gene.-Interactions:TXNIP has been shown to interact with Thioredoxin and ZBTB32.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome...
, POLR3GL
POLR3GL
Polymerase III polypeptide G -like also known as POLR3GL is a protein which in humans is encoded by the POLR3GL gene.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, LIX1L
LIX1L
Lix1 homolog -like also known as LIX1L is a protein which in humans is encoded by the LIX1L gene.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, RBM8A
RBM8A
RNA-binding protein 8A is a protein that in humans is encoded by the RBM8A gene.-Interactions:RBM8A has been shown to interact with IPO13, MAGOH and UPF3A.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, PEX11B
PEX11B
Peroxisomal membrane protein 11B is a protein that in humans is encoded by the PEX11B gene. It is involved in the regulation of peroxisome abundance.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, ITGA10
ITGA10
Integrin alpha-10 also known as ITGA10 is a protein that in humans is encoded by the ITGA10 gene.-Function:Integrins are integral membrane proteins composed of an alpha chain and a beta chain, and are known to participate in cell adhesion as well as cell-surface mediated signalling...
, ANKRD35
ANKRD35
Ankyrin repeat domain 35 also known as ANKRD35 is a protein which in humans is encoded by the ANKRD35 gene.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, PIAS3
PIAS3
E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.-Interactions:PIAS3 has been shown to interact with GFI1, RELA, Mothers against decapentaplegic homolog 3, Microphthalmia-associated transcription factor, HMGA2 and Mothers against decapentaplegic homolog...
, NUDT17, POLR3C
POLR3C
DNA-directed RNA polymerase III subunit RPC3 is an enzyme that in humans is encoded by the POLR3C gene.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome-Further reading:...
, RNF115, CD160
CD160
CD160 antigen is a protein that in humans is encoded by the CD160 gene.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome*1q21.1 duplication syndrome...
, PDZK1
PDZK1
Na/H exchange regulatory cofactor NHE-RF3 is a protein that in humans is encoded by the PDZK1 gene.-Interactions:PDZK1 has been shown to interact with AKAP10, FARP2, Sodium-hydrogen antiporter 3 regulator 1, SLC22A12, SLK, SLC22A4, CLCN3, PDZK1IP1, Cystic fibrosis transmembrane conductance...
, and GPR89A
Genes related to 1q21.1 deletion in the distal area are HYDIN2, PRKAB2
PRKAB2
5'-AMP-activated protein kinase subunit beta-2 is an enzyme that in humans is encoded by the PRKAB2 gene.-Interactions:PRKAB2 has been shown to interact with PRKAG2 and PRKAG1.-Further reading:...
, FMO5
FMO5
Dimethylaniline monooxygenase [N-oxide-forming] 5 is an enzyme that in humans is encoded by the FMO5 gene.-Further reading:...
, CHD1L
CHD1L
Chromodomain-helicase-DNA-binding protein 1-like is an enzyme that in humans is encoded by the CHD1L gene. It has been implicated in chromatin remodeling and DNA relaxation process required for DNA replication, repair and transcription....
, BCL9
BCL9
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.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. -Further reading:...
, ACP6
ACP6
Lysophosphatidic acid phosphatase type 6 is an enzyme that in humans is encoded by the ACP6 gene.-Interactions:ACP6 has been shown to interact with Integrin-linked kinase.-Further reading:...
, GJA5
GJA5
Gap junction alpha-5 protein is a protein that in humans is encoded by the GJA5 gene.- Function :This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of...
, GJA8
GJA8
Gap junction alpha-8 protein is a protein that in humans is encoded by the GJA8 gene. It is also known as connexin 50.-Interactions:GJA8 has been shown to interact with Tight junction protein 1....
, and GPR89B
GPR89B
Protein GPR89 is a protein that in humans is encoded by the GPR89B gene.-Further reading:...
.
Heredity
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 meiosisMeiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
. 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.
Research
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
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
and schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. 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.
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.
Research is done on 10-12 genes on 1q21.1 that produce DUF1220
DUF1220
DUF1220 is a protein domain of unknown function that shows a striking human-specific increase in copy number and may be important to human brain evolution. The copy number of DUF1220 domains increases generally as a function of a species evolutionary proximity to humans. DUF1220 copy number is...
-locations. DUF1220 is an unknown protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, which is active in the neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
near the neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
. 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
Macrocephaly
Macrocephaly , occurs when the head is abnormally large; this includes the scalp, the cranial bone, and the contents of the cranium.-Causes:...
) and schizophrenia (microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
). 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
Another relation between macrocephaly
Macrocephaly
Macrocephaly , occurs when the head is abnormally large; this includes the scalp, the cranial bone, and the contents of the cranium.-Causes:...
with duplications and microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...
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.