The National Foundation for Ectodermal Dysplasias is proud to grant $25,000 for a new research project led by Prof. Angus Clarke at Cardiff University and the All Wales Medical Genetics Service. He and his research team are testing a new way to diagnose x-linked hypohidrotic ectodermal dysplasia (XLHED) in utero.

You can read the details of the project below. Essentially, they seek to establish a non-invasive method for prenatal diagnosis rather than methods involving amniocentesis or chorionic villus sampling (CVS). In their proposed method, a woman who is pregnant and knows she is carrier for XLHED, would give a blood sample.

From that sample, researchers would extract DNA from the plasma portion. This DNA is a mixture from both the mother and the baby. Using precise methodology, they could then determine if the baby’s DNA included the gene for XLHED.

If successful, this method would help facilitate the upcoming clinical trial in which EspeRare plans to test ER-OO4 as an in utero treatment for XLHED.


Development of non-invasive prenatal diagnosis (NIPD) assay for X-linked hypohidrotic ectodermal dysplasia (XHED)

Researcher: Mrs. Sian Morgan, Consultant Clinical Scientist, Principal Investigator

All Wales Medical Genomics Service, University Hospital of Wales, Cardiff, Wales, United Kingdom, CF14 4XW

X-linked hypohidrotic ectodermal dysplasia (XLHED) is an x-linked disorder primarily affecting males and is the most common type of ectodermal dysplasia. XLHED is caused by mutations in the EDA gene, which result in defective ectodysplasin A formation or functioning.

Ectodysplasin A has a critical role in early embryonic development by mediating the interactions between two embryonic cell layers called the ectoderm and the mesoderm. When ectodysplasin A is non-functional, normal interactions between the ectoderm and the mesoderm are impaired, which leads to the defective development of hair, sweat glands and teeth.

There is substantial morbidity associated with XLHED in infant males, with at least 50% suffering failure to thrive and/or serious infections, especially pneumonia. Any treatment that can improve the development of teeth and the production of sweat glands and of mucus-secreting glands in the airways will bring substantial benefits.

Treating XLHED in Utero

A new paradigm of treatment – providing the missing protein at a few critical points in development, without the need for treatment long-term – has emerged for this disorder. Treatment in the newborn period is too late to be effective and a trial of treatment in utero is planned.

Current prenatal diagnosis of fetal genetic status depends on invasive diagnostic tests to collect a sample of the baby’s genetic material. Amniocentesis (taking fluid from around the baby) and CVS (taking a small sample from the placenta) both require the insertion of a needle into the womb and carry a small but not insignificant risk of miscarriage (0.5-1%).

Testing a Non-Invasive Method for Prenatal Diagnosis

Non-invasive prenatal diagnosis (NIPD) provides a safer way of diagnosing a single gene disorder in early pregnancy. It involves taking a blood sample from the mother and extracting the cell free DNA from the plasma component of the sample.

Cell free DNA (cfDNA) in the maternal plasma is a mixture of maternal and fetal DNA with the ‘fetal’ component representing around 3-10% of the total. NIPD uses highly sensitive and precise methods, such as next generation sequencing, to detect genetic alterations in the fetal DNA within the background of maternal DNA.

We wish to establish a NIPD assay to facilitate future trials of treatment in utero, in families where the mutation is already known. NIPD has already been successfully established as a prenatal diagnostic service in the United Kingdom for a number of rare diseases including cystic fibrosis, spinal muscular atrophy and Duchenne muscular dystrophy.

For these diseases, the relative haplotype dosage (RHDO) testing strategy is used. This involves using next generation sequencing (NGS) to identify a pattern of highly heterozygous single nucleotide polymorphisms (SNPs) on the affected chromosome then examining the same SNPs in the cfDNA sample.

The relative dosage of these SNPs in the cfDNA is then determined to identify whether or not the affected haplotype is over-represented in the maternal plasma indicating that the fetus has inherited the affected haplotype.

Our aim is to use this same methodology and apply it to the EDA gene.


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