CdLS Genetic Mutations

Cornelia de Lange Syndrome (CdLS) is a genetic disorder affecting 1 of every 10,000 births. CdLS is a disorder which can be caused by various genetic mutations. The number of possible causes, makes the disorder present uniquely in each individual. While 60% of CdLS cases are caused by a known genetic mutation, 30% of cases have an unknown cause.

Understanding Genes

More than 99% of CdLS cases are caused by de novo mutation, although it is possible for the disorder to be inherited depending on certain gene variations

"De novo" means "new,"

therefore, a de novo mutation is not genetically inherited.

A mutation on a female X chromosome may not manifest. Females have two X chromosomes, so the mutation may be masked.

Therefore, a mutation on the X chromosome in a male, would be more likely to present itself. This is because males have only one X chromosome.

The Genes of CdLS

“Cornelia de Lange Syndrome.” Genetic and Rare Diseases Information Center, U.S. Department of Health and                 Human Services, rarediseases.info.nih.gov/diseases/10109/cornelia-de-lange-syndrome.

 

“What Is CdLS?” Cornelia De Lange Syndrome (CdLS) Foundation, Inc., www.cdlsusa.org/what-is-cdls/.

NIPBL

60% of mutations causing CdLS are found on this gene, making it the most common gene affected

NIPBL is responsible for providing instructions to produce the protein, Delagnin

Delagnin: a protein which plays a role in the development of the limbs, skull, spinal column, and heart before birth

This gene mutation is found in many variations

The exact impact this mutation has on CdLS is unknown, but is likely related to developmental issues

Source: “NIPBL Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine,      National Institutes of Health, ghr.nlm.nih.gov/gene/NIPBL#conditions.

SMC1A

5% of mutations causing CdLS are found on this gene, making it the most common gene affected

SMC1A is responsible for providing instructions to produce a protein which is part of the Structural Maintenance of Chromosomes (SMC) family

There are more than 35 known variations of the mutation

Mutations likely interfere with the regulation of genes critical for development

Studies suggest these mutations cause a form of CdLS with mild features

Contrasted to NIPBL: (1) Less delays in development and growth, (2) Less likely to have major birth defects

Source: “SMC1A Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/SMC1A.

SMC3

SMC3 is responsible for providing instructions to produce a protein which is part of the Structural Maintenance of Chromosomes (SMC) family

 

This gene helps control chromosomes during cell division

This gene may also play an important role in stabilizing cells' genetic information, repairing damaged DNA, and regulating activity of genes essential for normal development

Source: “SMC3 Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/SMC3.

HDAC8

5% of mutations causing CdLS are found on this gene, making it the most common gene affected

HDAC8 is responsible for providing instructions to produce enzyme Histone Deacetylase 8

Histone Deacetylase 8: regulates structure and organization of chromosomes during cell division; may also play a role in stabilizing cells' genetic information, repairing damaged DNA, and controlling activity of genes crucial for development

There are 28 known variations of this mutation

All mutations seem to either reduce or eliminate the enzyme's activity which could impair its ability to regulate genes for normal development

Compared to NIPBL: Significant intellectual disability

Contrasted to NIPBL: (1) Less severe growth delays, (2) Fewer limb abnormalities, (3) Different facial features, (4) More likely to have delayed closure of the soft spot of head, (5) More widely spaced eyes, (5) Dental abnormalities

Source: “HDAC8 Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/HDAC8.

RAD21

This is a very uncommon cause of CdLS

RAD21 is responsible for providing instructions to produce a protein involved in regulating the structure and organization of chromosomes during cell division 

May also play an important role in stabilizing cells’ genetic info, repairing damaged DNA, and regulating the activity of certain genes essential for normal development

There are 8 known variations of the mutation

In some cases, this gene is missing from Chromosome 8 in each cell. In other cases, the mutation causes the protein to either be impaired or eliminated

It is suspected that altered gene regulation underlies many of the developmental problems which are characteristic of CdLS

Mutation of this gene causes relatively mild features 

Contrasted to NIPBL: (1) Less significant delays in development and growth, (2) Less likely to have major birth defects

Source: “RAD21 Gene - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/gene/RAD21#conditions.

 
 
 
 
 
 
 

ANKRD11

This gene mutation causes KBG Syndrome, which is incredibly rare

Relates to approximately .6% of CdLS cases

KBG Syndrome shares some symptoms and characteristics with CdLS; may be a comorbidity

Sources: Ansari, Morad, et al. “Genetic Heterogeneity in Cornelia De Lange Syndrome (CdLS) and CdLS-like Phenotypes with Observed and Predicted Levels of Mosaicism.” Journal of Medical Genetics, BMJ Publishing Group Ltd, 1 Oct. 2014, jmg.bmj.com/content/51/10/659.

 

“Genetic Information.” Cornelia De Lange Syndrome (CdLS) Foundation, Inc., www.cdlsusa.org/genetic-information/.