1q21.1 deletion syndrome

1q21.1 deletion syndrome or 1q21.1 (recurrent) microdeletion is a rare aberration of chromosome 1. Unique, the international rare chromosome disorder group, has 44 genetically confirmed registered cases of this deletion worldwide (september 2011).

In a common situation a human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 deletion syndrome one chromosome of the pair is not complete, because a part of the sequence of the chromosome is missing. 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 deletion is situated.

Next to the deletion syndrome, there is also a 1q21.1 duplication syndrome. While there is a part of the DNA missing with the deletion syndrome on a particular spot, there are two or three copies of a similar part of the DNA on the same spot with the duplication syndrome. 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.



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 deletion can be: the TAR-area for the TAR syndrome 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.

Typing
A common deletion is restricted to the TAR area or the distal area. This is a Class I-deletion.

In some cases the deletion is so large that both areas are involved, the so called Class II-deletion. There are some complex cases in which both the TAR area and the distal area are affected, while the area in between is normal. There are also some a-typical variants.

Symptoms
Recognised symptoms up till now are:
 * only one set of genes on the two chromosomes function (Haploinsufficiency)
 * TAR syndrome
 * Neurological-psychiatric problems: Autism; Schizophrenia; epilepsy; learning problems; Mental retardation — mild to moderate; Developmental delay — mild to moderate (milestones like sitting, standing and walking come at a later period in childhood); Children show an ataxic gait and fall down a lot
 * Dysmorphism: Slightly unusual facial appearance; disturbed growth; skeletal malformations; Small head (microcephaly); Prominent forehead; Bulbous nose; Deep-set eyes; Broad thumbs; Broad toes; Squint; Very flexible joints; Clavicular pseudoarthrosis (the collarbone doesn't develop normally) (Class II-deletion); An extra transverse crease of the fifth finger (Class II-deletion)); Problems with the development of the vagina (Müllerian aplasia)
 * Eyes: Cataracts
 * Heart abnormalities and cardiovascular anomalies (30% of the cases): Anomalous origin of the coronary artery (Class II-deletion)
 * Kidneys: kidney missing or floating kidneys
 * Cancer: Neuroblastoma
 * Sleep disturbances

Symptoms that are not confirmed: It is not clear whether the list of symptoms is complete. Very little information is known about the syndrome. The syndrome can have complete different effects on members of the same family.
 * Families with children who have 1q21.1 deletion syndrome report reflux (GERD)
 * There is recent information in which Noncompaction cardiomyopathy has been seen in combination with a ClassII-deletion.
 * During a pregnancy increased nunchal translucency and oligohydramnion were detected.

A common deletion is between 1.0–1.9Mb. Mefford states the standard for a deletion is 1.35 Mb. The largest deletion seen on a living human is over 5 Mb.

Related genes
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 PDE4DIP, HYDIN2, PRKAB2, PDIA3P, FMO5, CHD1L, BCL9, ACP6, GJA5, GJA8, NBPF10, GPR89B, GPR89C, PDZK1P1 and NBPF11.

Diagnostics
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 carrier of the syndrome, without any effect on the parent. 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 was identified with the child, because of an autism disorder or another problem, and later it appeared that the parent was affected as well. The parent never knew about it up till the moment that the DNA-test proved the parent to be a carrier.

In families where both parents have been tested negative on the syndrome, chances on 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%, because the syndrome is autosomal dominant. The effect of the syndrome on the child cannot be predicted.

The Syndrome can be detected with fluorescence in situ hybridization and Affymetrix GeneChip Operating Software.

For parents with a child with the syndrome, it is advisable to consult a physician before a next pregnancy and to do prenatal screening.

Management
Treatment of cause: Due to the genetic cause, no treatment of the cause is possible.

Treatment of manifestations: routine treatment of ophthalmologic, cardiac, and neurologic findings; speech, occupational, and physical therapies as appropriate; specialized learning programs to meet individual needs; antiepileptic drugs or antipsychotic medications as needed. Surveillance: routine pediatric care; routine developmental assessments; monitoring of specific identified medical issues.

Research
On several locations in the world people are studying on the subject of 1q21.1 deletion syndrome. The syndrome was identified for the first time with people with heart abnormalities. The syndrome has later been found with patients with autism and schizophrenia. Research is done on patients with a symptom of the syndrome, to find more patients with the syndrome.

It appears that there is a relation between autism and schizophrenia. Both autism and schizophrenia are caused by problems of the development of the embryo during the first month of pregnancy. Within 20 to 40 days after the conception, something goes wrong in the development of the embryo in the construction of both the body and the brain, which starts a chain reaction. Both diseases have the same cause.

In the genetic area, relations have been found between both autism and schizophrenia based on duplications and deletions of chromosomes. Statistical 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: schizophrenia), chromosome 22 on 22q11.21 (deletion (Velo-cardio-facial syndrome): schizophrenia/duplication: autism) and 22q13.3 (deletion (Phelan-McDermid syndrome): schizophrenia/duplication: autism). Further research confirmed that the odds on a relation between schizophrenia and deletions at 1q21.1, 3q29, 15q13.3, 22q11.21 en Neurexin 1 (NRXN1) and duplications at 16p11.2 are at 7.5% or higher.

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.

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

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.

Research on the genes CHD1L and PRKAB2 within lymphoblast cells lead to the conclusion that anomalies appear with the 1q21.1-deletionsyndrome:
 * CHD1L is an enzyme which is involved in untangling the chromatides and the DNA repair system. With 1q21.1 deletion syndrome a disturbance occurs, which leads to increased DNA breaks. The role of CHD1L is similar to that of helicase with the Werner syndrome
 * PRKAB2 is involved in maintaining the energy level of cells. With 1q21.1-deletion syndrome this function was attenuated.