• Researchers Identify Individuals Resilient to Severe Mendelian Childhood Diseases

Researchers Identify Individuals Resilient to Severe Mendelian Childhood Diseases

A genomic analysis of more than half a million people identified 13 individuals who appear to remain healthy despite carrying genetic mutations linked to severe childhood diseases.

Although the biological reasons for this resilience are not yet understood, the study provides a first step toward identification of genetic variants that protect against these diseases, and indicate a need to re-evaluate previous assumptions about the level of penetrance of some genetic mutations for diseases.

Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations. Rong Chen et al sought to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders.

They performed a comprehensive screen of 874 genes in 589,306 genomes. On April 11 in Nature Biotechnology, they report finding 13 adults who carry mutations for 8 severe Mendelian conditions with no reported clinical manifestation of the indicated disease.

The Economist wrote that the data, from European, Asian, and American sources, including the biotechnology company 23andMe and the Beijing Genomics Institute, yielded an initial pool of DNA sequences from 589,306 people. Of these, full genome sequences were only available for 3524 individuals. The remainder of the data came from medical screens that identified mutations in a selection of genes, or from exome studies.

Chen et al state that it is important to broaden genetic studies to systematically search for well individuals who are resistant to the effects of rare, highly penetrant, deleterious mutations. The identification of these resilient individuals and their protective factors could help elucidate the mechanisms of Mendelian diseases and also lead to new therapeutic strategies.

Of the identified candidate resilient individuals, 2 individuals were homozygous carriers of a splicing consensus acceptor mutation in DHCR7 (c.964-1G>C), which causes Smith-Lemli-Opitz syndrome (SLOS). SLOS is characterized by reduced serum cholesterol levels and increased serum levels of 7-dehydrocholesterol levels. Chen et al state that homozygous carriers of this splicing mutation are rarely seen, despite the high carrier frequency, and all manifest at the severe end of the disease phenotypic spectrum and are not known to survive through childhood.

The study identified 3 individuals who were homozygous for CFTR mutation c.1558G>T, associated with cystic fibrosis. One individual was found to be homozygous for the IKBKAP mutation c.2204+6 T>C. This Ashkenazi Jewish founder mutation is observed in nearly all cases of familial dysautonomia, a debilitating childhood-onset disorder. Another patient was homozygous for the c.769C>T mutation in AIRE, associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)—a childhood-onset disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease.

Three individuals were homozygous for the p.R279W SLC26A2 mutation. Compound heterozygotes or homozygotes of this mutation usually manifest severe skeletal dysplasia.

Individuals resistant to 3 autosomal dominant disorders were also detected. One person carried the KRT14 c.373C>T mutation, associated with the severe Dowling-Meara subtype of epidermolysis bullosa simplex (MIM131760). Another person carried the c.755Cright arrowG mutation in FGFR1, which causes Pfeiffer syndrome—a craniosynostosis disorder with manifestations in the distal extremities. One individual carried the SOX9 nonsense mutation p.Y440*, seen in patients with acampomelic campomelic dysplasia (MIM114290) — severe form of skeletal dysplasia.

In screening of the data sets, the authors also identified an individual with compound-heterozygous mutations in GBA (p.N409S and p.L483P) who had undergone routine carrier screening, but who had never been diagnosed with Gaucher disease. Upon clinical review, this individual was found to have subclinical manifestations of this disease

Chen et al conclude that finding mutations for severe early-onset diseases that are annotated as being completely penetrant, in putative nonpenetrant individuals, indicates that genetic modifiers could be more common than believed. Identification of resilient individuals could increase our understanding of Mendelian disease etiology and how we counsel others regarding such conditions.

The researchers said they don’t know for sure exactly why these people failed to develop the diseases that they seemed genetically destined for. These individuals might have other genetic factors that somehow suppress these disease-causing mutations.

The study’s co-author Stephen Friend told Scientific American “We now have tools that allow us to search for people who should have gotten sick, but didn’t. Study the healthy, don’t just study the sick.”

In an accompanying News & Views article, Daniel MacArthur writes that “the researchers could not recontact the majority of resilient individuals for further study because of a lack of necessary consent forms” and that “finding genetic superheroes will require other kinds of heroism — a willingness of participants to donate their genomic and clinical data and a commitment by researchers and regulators to overcome the daunting obstacles to data sharing on a global scale.”

The authors of the study have therefor launched The Resilience Project to screen the DNA of more than 100,000 healthy people and to detect factors that protect people from disease.

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