Informação

What causes Cornelia de Lange Syndrome


The genetic causes of CdLS are complex and research to fully understand all the genetic causes is still ongoing. The genetic make-up of a child cannot be changed after conception.

The CdLS spectrum has been associated with a change (mutation) in genetic material. Usually, CdLS is caused by a change in one of seven genes. Genes are individual genetic instructions in DNA that make us who we are. The seven genes associated with CdLS are: NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11 (R4). A change in one of these genes affects what is known as the cohesin protein complex (13,14,15,16,17,18).

The cohesin complex has many functions. One of these includes regulating the process of a fertilised egg dividing many times during the development of a baby. This process requires all of the DNA (genetic material present) to produce a second copy of itself before it divides. Changes to the genetic code can occur when the DNA is copied. The cohesin complex also regulates the expression, structure and organisation of a person’s genetic code (19,20,21,22).

If a change in genetic code affects one of the seven genes associated with the CdLS spectrum, the cohesin complex does not function properly. This can cause altered human development and is believed to be the underlying cause of CdLS and syndromes in the CdLS spectrum.

The known causes of CdLS are therefore called cohesinopathies. This is because changes in genes associated with CdLS affect the cohesin complex. However, not all cohesinopathies result in CdLS.

The cohesin complex has multiple parts. It is thought that there is a core centre which includes a ring which can open to hold the copies of DNA together until they divide, as well as associated proteins which help regulate the core centre. Genes always code for a single protein; in this case each gene related to CdLS codes for a different part of the cohesin protein complex.

Mutations that occur in genes can have small or large effects. There can be single small mutations (missense mutations) that change only a single part of the gene; these tend to produce proteins that might be able to do some of the work but not all, or that do the work slightly differently. Larger or more severe mutations (loss of function mutations) usually lead to more severe effects, such as resulting in no protein being produced at all. Deletions within a single gene, larger than mutations, can result in effects similar to a loss of function mutations or may have more severe effects. Specific gene variants (mutations or deletions in genes) have been identified in up to 84% of individuals with CdLS.

The seven known genes that are implicated in CdLS differ in the clinical features presented (See Table 2).

cornelia de Lange syndrome is a cohesinopathy

Fig. 4 | Cornelia de Lange Syndrome (CdLS) is a cohesinopathy(changes in genes associated with CdLS affect the cohesin complex). CdLS is caused by genetic variants that affect regulators of the cohesin complex. The structural components form a ring and cohesin subunits (such as STAG 1) attach to the ring and form part of the core complex.

Table 2: Comparison of the main clinical findings in individuals with different genetic variants of Cornelia de Lange Syndrome.

NR =Not reported
++++ = more than 90% of individuals
+++ = 70-89% of individuals
++ = 50-69% of individuals
+ = 20-49% of individuals
- = less than 20% of individuals

The different genes linked to Cornelia de Lange Syndrome
 NIPBLSMC1ASMC3BRD4HDAC8RAD21ANKRD11
Growth
Prenatal growth retardation++++++++++++
Short stature+++++++++++++
Microcephaly(decreased head size)++++++++++++++
Head and facial features
Wide skull shape+++++++++++++
Low frontal hairline+++++++++++++++
Arched, thick eyebrows++++++++++++++++++++
Meeting of the eyebrows in the midline+++++++++++++++++++++
Long eyelashes++++++++++++++++
Flattened nasal bridge++++++++A*
Nose tip upturned++++++++++++++++
Wide tip of nose+++++++++++
Long, smooth philtrum (vertical indentation in the middle area of the upper lip)+++++++++++++++
Thin upper lip++++++++++++++++++
Downturned corners of the mouth+++++++++++++++
Highly arched palate+++++++++
Widely spaced teeth+++++++B*
Small, underdeveloped jaw++++++++++
Low-set and malformed ears++++++
Body
Absence of few or all fingers+
Small hands++++++++++++++++++++
Thumbs attached close to wrists+++++++++++++
Bent or shorter fifth finger++++++++++++++
Small feet+++++++++NR+++++++
Abnormally increased hair growth+++++++++++++++
Heart problems++++++
Abnormal vertebrae (bones forming the backbone)++++++
Cognition and behaviour
Intellectual disability/learning disability (any degree)+++++++++++++++++++++++++
Autism spectrum disorder++++++
Self-injurious behaviour++++NR++++
Stereotypic movements (repetitive, simple movement that can be suppressed)++++NRNR

A* = Prominent nasal bridge rather than flattened nasal bridge
B* = Teeth are not widely spaced but are larger than normal

NIPBL

The NIPBL gene codes for a protein which is part of the regulatory centre of cohesin and, along with another gene (MAU2) helps the ring to be loaded onto the duplicated DNA. Changes (mutations) in NIPBL can be found in approximately 70% of individuals with CdLS. Classic CdLS is usually caused by changes in NIPBL (13,14). The missense mutations (single small mutations) cause milder phenotypes than the loss of function mutations, as described here . Deletions may occur in NIPBL in about 3% of those with CdLS. Also, there are quite a few people with classic CdLS who have been found to have mosaicism for mutations in NIPBL, which means that not all of the cells tested show the mutation (e.g. the mutation is unable to be found in a blood sample, but can be detected on a cheek swab which takes cells from the inside of the cheek.

While individuals with the classic CdLS phenotype are likely to have changes in NIPBL, individuals with changes in the other causative CdLS genes can also fulfil the criteria for classic CdLS.

SMC1A

SMC1A is responsible for producing and maintaining the core component of the cohesin complex ring. Changes in SMC1A have been found in approximately 5% of individuals with CdLS (3).

Many individuals with changes in SMC1A usually display a non-classic phenotype (3,15,16,24,29) and have fuller eyebrows, less shortening of the nasal bridge and a rounder face compared to individuals with changes in NIPBL.

40% of individuals with changes in SMC1A display a phenotype that resembles Rett Syndrome (another neurodevelopmental disorder associated with intellectual disability) more than CdLS (3,30,31).

The gene SMC1A is on the X chromosome. There are two copies of the X chromosome in all of the cells of females and only one in all of the cells of males. For the majority of genes, one of the X chromosomes in females is inactivated (turned off) to have the same balance as in males. However, some genes are not inactivated and that is the case for SMC1A (32). This means that males are typically more severely affected than females, as females have two copies of the gene, with one likely to not have a mutation (3,15). There has been a report of mosaicism for a variant in this gene in one person only (16).

SMC3

SMC3 is responsible for producing the other major part of the ring of the core cohesin complex. Changes in SMC3 were initially reported in a single individual with non-classic CdLS (16) and changes to this gene are an uncommon cause (1%) of non-classic CdLS (33).

Changes in SMC3 have however, been found in individuals with intellectual disability, short stature (height) and congenital abnormalities (birth defects) who do not fulfil the criteria for non-classic CdLS (24,33). Changes in SMC3 are typically linked to missense mutations (single small mutations; as described here) (33).

RAD21

RAD21 also forms part of the core cohesin complex (34). Changes in RAD21 have been found in a small percentage (1-2%) of causes for CdLS. Individuals with changes in RAD21 are reported to have a non-classic CdLS phenotype (17,24,35). Both loss of function and missense mutations have been reported, as well as deletions within the RAD21 gene (36). It is difficult to look at the relationship between this specific gene mutation and clinical characteristics due to the low number of individuals reported to have a mutation in the RAD21 gene.

BRD4

BRD4 codes for a protein that associates with NIPBL and likely attaches to the protein once the cohesin ring has bound the DNA (37). The number of reported individuals with variants involving BRD4 is small, but a deletion that includes BRD4 has an atypical phenotype for CdLS.

HDAC8

Changes to the gene HDAC8 were first reported in individuals with classic and non-classic CdLS (18). HDAC8 is also on the X chromosome but it can be inactivated. It is important to note that changes on HDAC8 may also result in characteristics that do not resemble CdLS (39). Currently, variants in HDAC8 have been found in about 5% of individuals with CdLS (24,38,39,40,41,42).

There is a wide variation in the phenotype shown by individuals with a mutation in HDAC8. Typically, individuals with a mutation in HDAC8 have a non-classic CdLS phenotype, but some individuals do fulfil the criteria for classic CdLS. In addition to the features of CdLS, individuals with a change in HDAC8 may show some other distinctive features.
These include: A large anterior fontanel (the soft spot on an infant’s head before the skull bones meet at approximately 2 years of age), widely spaced eyes or a happy personality.

Because HDAC8 is randomly inactivated when there is more than one X chromosome (41), both males and females can be affected when there is a mutation in this gene. Some of these females can be completely healthy, and in those cases, most have non-random inactivation of the HDAC8 with the mutation (41,42).

ANKRD11

Changes in the gene ANKRD11 have been reported in several individuals with a non-classic CdLS phenotype (24,43 ), and others have been noted in several clinical observations. Individuals with changes in ANKRD11 show features that overlap with the facial characteristics and suggestive features of CdLS (see Box 1).

Other genes

Changes in several other genes associated with a phenotype of the CdLS spectrum have also been found. Individuals with changes to these genes show a small number of clinical features seen in CdLS.

  • Changes in the gene EP300 have been found in individuals with some features suggestive of CdLS (44).
  • Changes in the gene AFF4 have been found in several individuals with CHOPS syndrome. “CHOPS” stands for cognitive impairment (e.g. problems with memory, communication and thinking), coarse facial features, heart defects, obesity, pulmonary involvement, short stature and skeletal dysplasia (disorder that affects bones/joints and hinders growth). CHOPS syndrome includes features which overlap with CdLS (45).
  • Changes in the gene NAA10 have been found in some individuals with some resemblance to CdLS that is limited to the region around the eyes (5).
  • Changes in the gene TAF6 have been found in two families with children who showed features that overlap with CdLS (4).

Mosaicism

Mosaicism, means there are different groups of cells with different genetic make-up in a person. This means that some cells in the person will have the mutation and others will not. Mosaicism has been found to occur frequently in CdLS (23). Approximately 15-20% of individuals with classic features of CdLS have mosaic changes in NIPBL; and although it is rare, individuals with CdLS can also have mosaic changes in SMC3, RAD21 or SMC1A. These mosaic changes cannot be found using genetic testing that examines an individual’s DNA from their white blood cells (23,24,46).

In some circumstances, if an individual is found to be mosaic for a mutation, it is thought that there could be a variation in the severity of the clinical findings. However, there is no evidence that this occurs in CdLS. It is suggested that there may be a selection against these gene changes occurring in blood cells (41,23,46 ), meaning they may not be identified using blood tests. Genetic testing can evaluate DNA for mosaicism by examining fibroblasts (connective tissue cells), buccal cells (cheek cells) or bladder epithelial cells (cells in urine) instead (R5) (23,24).

Family Recurrence Risk

Genetic counselling should be offered to all families with a family member with CdLS. Genetic counselling is when prospective parents are given advice about the risks of having a child with a genetic disorder. The International CdLS Consensus Group advises that the recurrence risk of CdLS in a future child differs depending on which gene is involved.

The genes (NIPBL, SMC3, RAD21, BRD4 and ANKRD11) that are not on the X chromosome are autosomal (dominant) genes, meaning that if a mutation is fully present, the clinical effects will occur. Most of the time the mutation will be new in the family when a child is born with CdLS. Families have been reported to have more than one child with CdLS, with parents unaffected (47,48). This is due to a small population of some of a parent’s eggs or sperm cells carrying the mutation (this is called germline mosaicism). For this reason, the recurrence risk for future children is never said to be zero. There also could be a very mildly affected parent, with a mutation in one of these genes, who would have a 50% (1 in 2) chance of passing on that mutation in each subsequent pregnancy. The authors’ joint experience based on 560 families having a child with a variant in NIPBL is that the recurrence risk due to germline mosaicism is 0.89% (slightly less than 1 in 100).

For the genes (SMC1A and HDAC8) on the X chromosome (X-linked), most of the time the mutation is new in the family. If the mother is unaffected but carries the mutation, the recurrence would be 50% (1 in 2) with each subsequent pregnancy. Sometimes genetic counselling is difficult, because affected siblings can be variably affected clinically (3,35,41,42). This is also true for families with RAD21 mutations.

If no molecular testing has been done, the total overall recurrence risk for CdLS has been calculated in the past to be 1.5% (1½ in 100) (49) (R6).

summary section

Causes of Cornelia de Lange Syndrome recommendations:
R4: Classic CdLS is usually caused by variants in NIPBL; however, variants in one of six other genes – SMC1A, SMC3, RAD21, BRD4, HDAC8 or ANKRD11/ – should also be considered, as they may lead to a similar phenotype.
R5: Mosaicism should be considered in individuals with CdLS in whom a variant in a gene known to cause CdLS cannot be detected in blood cells, in which case other tissues such as fibroblasts (skin), buccal (cheek) cells or bladder epithelial cells from urine should be studied.
R6: Genetic counselling should be offered to all families with a family member with CdLS. Families should be counselled that the recurrence risk of CdLS differs depending on the gene involved. In the non-X-linked forms, the recurrence risk is 0.89% due to germline mosaicism. Autosomal dominant inheritance of CdLS does occur, meaning if one copy of the mutation is present, the individual will show clinical effects. In clinically diagnosed individuals with CdLS, the recurrence risk is 1.5%.

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Adapted from: Kline, A. D., Moss, J. F., Selicorni, A., Bisgaard, A., Deardorff, M. A., Gillett, P. M., Ishman, S. L., Kerr, L. M., Levin, A. V., Mulder, P. A., Ramos, F. J., Wierzba, J., Ajmone, P.F., Axtell, D., Blagowidow, N., Cereda, A., Costantino, A., Cormier-Daire, V., FitzPatrick, D., Grados, M., Groves, L., Guthrie, W., Huisman, S., Kaiser, F. J., Koekkoek, G., Levis, M., Mariani, M., McCleery, J. P., Menke, L. A., Metrena, A., O’Connor, J., Oliver, C., Pie, J., Piening, S., Potter, C. J., Quaglio, A. L., Redeker, E., Richman, D., Rigamonti, C., Shi, A., Tümer, Z., Van Balkom, I. D. C. and Hennekam, R. C. (2018).

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Modificado por Gerritjan Koekkoek em 2023/08/29 13:49
Criado por Gerritjan Koekkoek em 2019/03/27 15:09