The number of human genetic diseases unraveled by next-generation sequencing skyrocketed this year. Several factors contributed to this growth, two of which were the ever-increasing throughput of sequencing instruments and widespread availability of commercial exome platforms. A number of large-scale initiatives to discovery disease genes by exome sequencing, particularly for Mendelian disorders, got off the ground. I’d also argue that the rapid pace of discovery is also aided by a growing acceptance of sequencing as a clinical tool.
A PubMed search restricted to keywords “exome” and “sequencing” and year 2011 returned over 100 publications, of which more than 60 were studies linking genetic variation to human disease. I’ve whittled the list down to around 40 and (after consulting a medical dictionary for most) divided them down by rough disease categories.
The largest of these was what I call “developmental disorders” – mental retardation, dysplasia (abnormal growth), dyskinesia (impaired movement), and the like. There were at least 14 gene-disease associations published this year, many of them in the Americal Journal of Human Genetics.
Familial Cancer Syndromes
Sequencing of individuals with hereditary cancer syndromes enabled the identification of some new cancer susceptibility genes. This category will undoubtedly explode in the coming year as thousands of cancer patients have their genomes or exomes sequenced.
Next up, metabolic disorders. Interestingly, a study by Vissers and colleagues linked germline variants in IDH1 — a gene recurrently mutated in leukemia, glioblastoma, and other cancers — to “metaphyseal chondromatosis”, a rare disorder of severe bone dysplasia, neurodevelopmental problems, and strongly increased secretion of D-2-hydroxy-glutaric acid.
Blood and Lymphatic Deficiencies
Several inherited deficiencies of the blood and lymphatic system were linked to causal mutations. What I liked about this category was that half of the publications came out in “non-genome” journals — Blood and Haematologica — indicating that medical specialists in the field recognize the importance of (and in some cases, are already applying) exome sequencing to study such diseases.
Neurological disorders win the prize for making me look up the layman’s term for virtually every disorder whose causal gene was pinpointed by sequencing this year. These include such genes as lipofuscinosis (excessive accumulation of lipopigments), paraparesis (lower limb paralysis), and dystonia (abnormal muscle tone leading to movement and stature problems).
New disease genes were identified for several muscle fiber diseases (myopathies), including cardiomyopathy (heart muscle deficiency, usually fatal) and ophthalmoplegia, in which the muscles that control eye movement are paralyzed. Interestingly, the two mitochondrial cardiomyopathy disease genes (MRPL3 and AARS2) reported both encode products required for mitochondrial ribosomal function (MRPL3 encodes a ribosomal sub-unit, while AARS2 encodes a t-RNA synthetase).
The last disease category I’ll mention is that of vision (loss) disorders. A number of new disease-causing genes were identified this year, mostly by exome sequencing. Two studies were particularly interesting. First, Bowne and colleagues (including myself) identified a mutation in the RPE65 gene causing autosomal dominant retinitis pigmentosa. This gene had only been associated with autosomal recessive RP; finding that it acts in dominant fashion suggests previously unknown routes of disease pathogenesis and new therapeutic possibilities. Second, Shi et al linked mutations in the ZNF644 gene to high myopia (severe nearsightedness), a common cause of blindness. Have you ever heard of a ZNFxxx gene that actually does something? Most of the time, you look these up and it says “May be involved in transcriptional regulation.” It’s good to know that at least one of them serves a purpose, namely, keeping most of us from virtual blindness.
And there you have it. The genetic basis of dozens of inherited disorders, pinpointed by next-generation sequencing. There is simply no plausible way to deny the importance of next-generation sequencing to advancing human health and medicine. One can only imagine what we’ll know by next December, as large federally-funded initiatives ramp up their efforts to systematically apply exome and whole-genome sequencing to inherited disorders.
Shendure, J. (2011). Next-generation human genetics Genome Biology, 12 (9) DOI: 10.1186/gb-2011-12-9-408