Author: David Bennett-Orphan diseases/UK specialist
New-born screening for rare disorders

New-born screening for rare disorders

New-born screening for rare disorders Date:07 January 2016
What are the implications of the genomics revolution?
Two aspects of the genomics ‘revolution’ we are now living in are intertwined: the ability to diagnose rare genetic conditions and the technological capability to produce pharmaceutical grade proteins to treat many of these disorders. Orphan Drug legislation has been an important contributor to the development of treatments for patients with severe and life-limiting disorders. For healthcare policy makers and commissioners of services, integrating these rapid technological advances into the healthcare system is stretching resources. New thinking is needed on funding, organization of services and ethics.

Many rare genetic diseases are categorized as inborn errors of metabolism. They are often degenerative, with signs and symptoms appearing during childhood. Even if specific treatments for the disease are not yet available, many children can benefit from the care of medical specialists with experience in managing these complex diseases. Provision of optimal treatment usually demands early diagnosis. However, the differential diagnosis of so many of these conditions is not easy, even for hospital specialists. One option is to increase the number of conditions included in national new-born screening (NBS) programmes. Antenatal screening is a familiar practice for selected, at-risk, women, but the potential for increasing the number of pregnancy terminations makes extending the range of conditions included in antenatal screening contentious (see ‘Cautionary tale’ below).

There are several thousand rare genetic disorders. Very few are covered by national NBS – in the UK only nine. This is low, even compared with the number of conditions covered in other countries. According to an EU-wide survey, in 2011 38 conditions were screened for, with Austria leading with 29 conditions on its national NBS panel. There is reason to be cautious in adding conditions to the list. The national screening committee considers specific inclusion criteria. These are typically based on a set of criteria that were developed for the WHO in 1968 by Wilson and Jungner. The criteria take into account the severity of the condition, availability of treatment(s), existence of diagnostic facilities, and whether there is a recognizable latent stage of disease. Current NBS is still largely based on biochemical evaluation of blood spot samples.

With the costs of high-resolution genetic screening falling, genome analysis at birth to identify the presence of known disease-causing mutations has become realistic, if not for national health authorities, then for parents with modest disposable income. Generating such a rich source of data on a child’s genetic inheritance poses practical and ethical concerns. Findings of unknown significance today might become more relevant as knowledge of the genotype-phenotype link emerges, perhaps many years in the future. Should individuals be traced and provided with an update on their risk on a continual basis? It should be borne in mind that the individual would not, as a child at the time of initial testing, have given informed consent.

It is possible that parents will take the initiative and seek NBS privately. Partly in preparation for this scenario, a study is underway in the United States (BabySeq) to evaluate the outcomes of genome sequencing in new-borns for 1,700 genes linked to serious disorders that start in childhood. The consequence of knowing about a new-born’s susceptibility to hundreds of disorders is clearly a quantum leap from current NBS practice. The BabySeq project aims to help understand the implications of such knowledge before parents rush to take advantage of the new technology.

Other significant developments include the UK 100,000 genome project. The remit of this project is to sequence 100,000 complete genomes of patients with rare diseases and cancers. Eleven centres have been selected to deliver the project and to date over 6,000 genomes have been sequenced ( This project promises to provide a conclusive diagnosis for a rare and inherited disease that was not possible before; the treatment of cancers will change significantly.
The pace of medical advances continues to open up more opportunities for improving patient care and, in certain cases, is resulting in cost savings. The application of genome analysis to new-born screening will allow clinicians to intervene earlier in a greater number of progressive diseases. However, at least in the short term, it’s easy to envisage the continued advances in genomics leading to unintended consequences, creating ethical dilemmas and stretching public healthcare resources.

A Cautionary Tale
Turner syndrome

Turner syndrome (TS) describes a complex of features affecting girls with all or some of the following manifestations: short stature, early loss of ovarian function/failure, skeletal abnormalities and certain heart defects. Intelligence is normal. The cause is the loss of all or part of the X chromosome. TS is not routinely screened for either pre- or post-natally. As a result, particular girls with less severe external signs of TS may not be identified until they are well into childhood, typically in such cases, around the time of normal puberty. Other than specific difficulties arising from some features of TS, girls generally lead fulfilling and independent lives. In other words, parents of a girl with TS have every reason to look forward to their parenting years.
However, the Turner Syndrome Support Society [TSSS] can attest to the fact that parents do sometimes receive ill-informed advice from healthcare professionals that paints a pessimistic view of the outlook for a girl with TS. The screening of nuchal fold scans to identify foetuses affected by Downs syndrome has increased the uptake of karyotyping (counting chromosomes), and as a result more cases of TS have been identified. In the absence of accurate advice on the outlook for a girl with TS, this has led to parents opting for termination. This is an example of the danger of pre-natal screening when combined with poor advice.