Genotype-Phenotype Correlations in Cornelia de Lange Syndrome

Our bodies are made up of billions of cells and within each cell there are chromosomes which are the structures that hold all of our approximately 20,000 genes and genetic information. Genes function as the body’s instruction manual telling our body how to grow and develop.

We have two copies of each gene as we get one set from our mothers and one set from our fathers. Genes are made up of genetic material, called DNA, and they serve as the blueprint from which proteins are made. Proteins are the basic building blocks of the human body performing specific functions so that our bodies work properly controlling everything from our heartbeat to determining our eye color (Figure 1).

Figure 1. Cells contain DNA material which is organized into genes. Genes make proteins which are the basic building blocks of the body responsible for making our bodies work properly.
Figure 1. Cells contain DNA material which is organized into genes. Genes make proteins which are the basic building blocks of the body responsible for making our bodies work properly.

Sometimes changes (or mutations) spontaneously occur in genes that prevent them from working properly altering the proteins that are made. As a result, this a ects various bodily functions including growth and development. Currently, mutations in  ve di erent genes, NIPBL, SMC1A, SMC3, HDAC8 and RAD21, have been associated with Cornelia de Lange Syndrome (CdLS) (and several others, such as AFF4, TAF1 and TAF6 that have been associated with clinical pictures similar toCdLS).  The association between the presence of a certain mutation or mutations in a speci c gene (genotype) and the resulting presence, absence or severity of symptoms or clinical features (phenotype) is called a “genotype- phenotype correlation”.
Now that there are  ve genes known to be involved in CdLS certain genotype-phenotype correlations have been observed for each of the genes. Changes in these  ve genes are found in approximately 65 percent of individuals with a clinical diagnosis of CdLS, with the vast majority being caused by mutations in NIPBL.


Individuals with classic  ndings of CdLS, including characteristic facial features and limb anomalies, are likely to have a change identi ed in the NIPBL gene. However, changes (or mutations) in NIPBL have been found in individuals with both classic and mild presentations.  e degree of severity depends on the speci c type of mutation that occurs and where the mutation falls within the NIPBL gene.
A truncating (or frameshift) mutation is one type of mutation that tends to have a more signi cant e ect on the gene that can ultimately block protein production.  erefore individuals with truncating mutations typically present with a more classic or severe form of CdLS.
Missense mutations are a di erent type of mutation which generally only slightly changes the protein.  erefore, individuals with missense mutations typically present with milder forms of CdLS, since their proteins likely retain some residual function.

SMC1A and SMC3

Individuals with SMC1A or SMC3 mutations typically have fewer structural differences, such as a limb difference or heart difference. Such individuals also tend to present with less signi cant growth restriction than those with NIPBL mutations. However, individuals with SMC1A or SMC3 mutations will still typically have intellectual disability that can range from moderate to severe [Deardor  et al 2007].
Subtle facial features in individuals with SMC1A or SMC3 mutations may di er than those observed in “classic” CdLS caused by NIPBL mutations and can include slightly  atter and broader eyebrows with a broader and longer nasal bridge [Rohatgi et al 2010]. Speci cally, individuals with SMC3 mutations often have subtle or absent synophyrs (connecting eyebrows), wider nose with a rounder tip, and a well-formed philtrum (vertical groove between the base of the nose and upper lip).


Individuals with mutations in RAD21 typically do not have major structural di erences. Individuals with RAD21 mutations have milder cognitive impairment compared to those with “classic” CdLS.  ese individuals typically display growth retardation, minor skeletal anomalies, and facial features that overlap with CdLS. [Deardor  et al 2012].


Individuals with mutations in HDAC8 have facial features which overlap with CdLS but typically display delayed closure of the anterior fontanel (the opening or “soft spot” on the top of the head in babies which typically closes around one year of age), hooded eyelids, a wider nose, varying pattern of skin pigmentation, and friendly personalities. Growth restriction also tends to be less signi cantly a ected with this gene and a lower frequency of microcephaly (small head circumference) is reported.
In females, the severity of clinical presentation caused by mutations in HDAC8 is variable, since this gene is on the X chromosome and females have two X chromosomes while males have only one X chromosome and a Y chromosome. Since women have two X chromosomes in every cell, they randomly shut o  one copy of the X chromosome (called X-inactivation).  erefore, depending on how many X chromosomes with the mutation versus those without the mutation are inactivated will directly in uence the severity of their clinical presentation. ( ough SMC1A is also located on the X chromosome this X-inactivation process does not apply to the SMC1A gene).

NIPBL mosaicism

A recent study led by Dr. Raoul Hennekam in the Netherlands [Huisman et al 2013] has found that mosaicism for NIPBL mutations may be found in up to 30 percent of individuals with CdLS who have tested negative in the blood for mutations in the known CdLS genes. Mosaicism means that an individual has a change in a gene which is present in only some but not all of the cells in their body. If an individual is mosaic for a change in NIPBL, we may not be able to identify this change by testing only their blood; instead, we may need to test other cells from other tissues such as cheek cells, also called buccal cells.
Depending on the number of cells carrying the mutation and the tissues involved, an individual with NIPBL mosaicism can theoretically present with a more mild form of CdLS. However, additional research is needed in this area since only a few patients with NIPBL mosaicism have been identi ed thus far.

What it all means

While clinicians and researchers have reported these genotype-phenotype correlations (summarized in Figure 2) it is important to note that they are generalities and are often true but these “rules” are also frequently broken. We have seen children with severe (truncating or frameshift) mutations in NIPBL who have a mild clinical picture (phenotype) and conversely also seen children with mild (missense) mutations in NIPBL who have a very severe clinical picture.

Figure 2. With five genes known to be involved in CdLS certain genotype- phenotype correlations have been observed for each of the genes..
Figure 2. With five genes known to be involved in CdLS certain genotype- phenotype correlations have been observed for each of the genes.

There is still much work to be done to fully understand the correlations between the genotype and phenotype in individuals with CdLS, but there are general principles emerging and clinicians are getting better at using this information to help provide some guidance and prognostic information to families.

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Ian Krantz, MD, and Sarah Noon, MS
Ian Krantz, MD, and Sarah Noon, MS

MS, CGC, Center for CdLS and Related Diagnoses, Children’s Hospital of Philadelphia; members, CdLS Foundation Clinical Advisory Board,

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Ultima modifica di Gerritjan Koekkoek il 2021/04/08 14:24
Creato da Gerritjan Koekkoek il 2015/11/05 20:53


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