From new screens to discovered genes: The successful past and promising present of single gene disorders

Abstract

Prenatal screening for single gene disorders, which include over 10,000 diverse diseases, presents a great challenge. The major approach to identifying high‐risk groups for diseases, from Tay Sachs Disease to sickle cell disease, has historically centered on ethnic‐based screening. A major concern in an ethnic‐based approach is that carriers belonging to less‐traditionally considered populations will be missed. In the United States, the paradigm for a more modern pan‐ethnic approach has become exemplified by cystic fibrosis (CF), although considerable debate about future directions remains. CF screening brings several additional issues to the forefront, including that the largest molecular prenatal genetic screening program is based on a single gene disorder that is not necessarily severely disabling. On the other hand, several devastating disorders where screening is indeed available remain relatively inaccessible to prenatal patients in the general population. Future candidates to consider for broad‐based screening programs include spinal muscular atrophy (SMA), fragile X, and inborn errors of metabolism. As prenatal screening for single gene disorders expands, issues to consider include inclusion criteria and risk versus benefit. © 2007 Wiley‐Liss, Inc.

Carrier Screening for Spinal Muscular Atrophy (SMA) in 107,611 Pregnant Women during the Period 2005–2009: A Prospective Population-Based Cohort Study

“…This severe neuromuscular disease affects 1 in 5,000 to 1 in 10,000 live births and is associated with an overall carrier frequency of 1 in 35 to 1 in 50 in the general population [2], [3], [4], [5]. SMA is caused by degeneration and loss of the alpha motor neurons of the anterior horn cells of the spinal cord, leading to progressive symmetric proximal muscle weakness and atrophy [6]. Currently, there is no treatment for the disease [6].…”

“…SMA is caused by degeneration and loss of the alpha motor neurons of the anterior horn cells of the spinal cord, leading to progressive symmetric proximal muscle weakness and atrophy [6]. Currently, there is no treatment for the disease [6]. Type I SMA (Werdnig-Hoffman disease, OMIM 253300) manifests as severe muscle weakness and hypotonia with onset in early infancy, and fatal respiratory failure usually before 2 years of age.…”

Genetic Screening

“…A new technique, extraction of fetal DNA from maternal serum (134), is also likely to cause debate because it creates a noninvasive method to accomplish prenatal testing for a wide array of genetic conditions. Genomic technology will also have an impact on carrier testing: assessment of multiple carrier states will become increasingly feasible, and, as tests become more comprehensive, tailoring testing to ethnicity will no longer be necessary (135). A prototype of a genome-scale carrier test has been described, in which sequencing technology was used to identify carrier states for 448 recessive childhood diseases (136).…”

Genomic Medicine in Prenatal Diagnosis

“…One candidate is spinal muscular atrophy, an autosomal recessive disease with a carrier frequency around 1:50 in the United States, Europe, and Asia. 13 Not only is this condition a severe progressive neurodegenerative disorder with little available treatment, prenatal testing can detect about 94% of cases. The high incidence, severity of disease with little available treatment, and ease of genetic testing make this a very attractive candidate.…”