Disease-causing Mutations Discovered by NGS in 2011

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.

Developmental Disorders

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.

Developmental Disorders
SMOC2 Major dental developmental defects Bloch-Zupan et al. AJHG.
SYT14 Spinocerebellar ataxia with psychomotor retardation Doi et al. AJHG.
TECR Non-syndromic mental retardation Caliskan et al. Hum Mol Genet.
PRRT2 Paroxysmal kinesigenic dyskinesia Chen et al. Nat Genet.
SERPINF1 Osteogenesis imperfecta Becker et al. AJHG.
KIF22 Spondyloepimetaphyseal dysplasia with joint laxity Min et al. AJHG.
KAT6B Say-Barber-Biesecker syndrome Clayton-Smith et al. AJHG.
POP1 Novel skeletal dysplasia Glazov et al. PLoS Genet.
CCDC8 3-M syndrome Hanson et al. AJHG.
SLCO2A1 Primary hypertrophic osteoarthropathy Zhang et al. AJHG.
WDR62 Recurrent polymicrogyria Murdock et al. Am J Med Genet A.
FAM20A Amelogenesis imperfecta O’Sullivan et al. AJHG.
SHROOM3 Heterotaxy Tariq et al. Genome Biol.
MCT8 X-linked leucoencephalopathy Tsurusaki et al. J Med Genet.

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.

Hereditary Cancer Syndromes
MAX Hereditary pheochromocytoma Comino-Mendez et al. Nat Genet.
RET Familial medullary thyroid carcinoma Qi et al. PLoS One.

Metabolic Disorders

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.

Metabolic Disorders
ACSF3 Combined malonic and methylmalonic aciduria Alfares et al. J Med Genet. and Sloan et al Nat. Genet.
MTHFD1 Novel inborn error of folate metabolism Watkins et al. J Med Genet.
IDH1 Metaphyseal chondromatosis with aciduria Vissers et al. Am J Med Genet A.

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.

Blood and Lymphatic Disorders
NBEAL2 Gray platelet syndrome Albers et al. Nat Genet.
GATA2 Dendritic cell, monocyte, B and NK lymphoid deficiency Dickinson et al. Blood.
MPL Familial aplastic anemia Walne et al. Haematologica.
GJC2 Primary lymphoedema Ostergaard et al. J Med Genet.

Neurological 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).

Neurodegenerative Disorders
DNAJC5 Adult neuronal ceroid-lipofuscinosis Benitez et al. PLoS One.
KIF1A Hereditary spastic paraparesis Erlich et al. Genome Res.
GCDH Early-onset generalized dystonia Marti-Masso et al. Hum Genet.
FA2H Fatty acid hydroxylase-associated neurodegeneration. Pierson et al. Eur J Hum Genet.
AFG3L2 Spastic ataxia-neuropathy syndrome Pierson et al. PLoS Genet.
BANF1 Hereditary progeroid syndrome Puente et al. AJHG.
DYNC1H1 Dominant axonal Charcot-Marie-Tooth disease. Weedon et al. AJHG.


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).

MRPL3 Mitochondrial cardiomyopathy Galmiche et al. Hum Mutat.
AARS2 Infantile mitochondrial cardiomyopathy Gotz et al. AJHG.
RRM2B Progressive external ophthalmoplegia Takata et al. Genome Biol.
BAG3 Dilated cardiomyopathy Norton et al. AJHG.

Vision-loss Disorders

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.

Vision Disorders
RPE65 Retinitis pigmentosa with choroidal involvement Bowne et al. Eur J Hum Genet.
MAK Retinitis pigmentosa Ozgul et al. AJHG.
ZNF644 High myopia Shi et al. PLoS Genet.
MAK Retinitis pigmentosa Tucker et al. PNAS.
Leber congenital amaurosis Wang et al. Hum Mutat.
DHDDS Retinitis pigmentosa Zuchner et al. AJHG.

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

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Ryan Morin
Ryan Morin

Hi Dan.

Depending on how complete you want to be, you might also want to include the Tiacci hairy cell leukemia paper. Though there was only a single discovery case (i.e. one exome), they found ~100% recurrence of BRAF V600E mutations in the disease.

Tiacci, E., Trifonov, V., Schiavoni, G., Holmes, A., Kern, W., Martelli, M.P., Pucciarini, A., et al., 2011. BRAF mutations in hairy-cell leukemia. N Engl J Med, 364(24), pp.2305–2315.

Joanne Manaster (@sciencegoddess)
Joanne Manaster (@sciencegoddess)

This is a great list. I will share with my students in my course on the human genome. They are certified teachers who will certainly take this information back to their classrooms to show the practicality of NGS these days.




Here's another for you:

STRA6 mutation in Microphthalmia, anophthalmia, and coloboma (MAC)

PMID: 21901792

Dan Koboldt
Dan Koboldt

Neil, thanks for the comment. Your wish is my command! Links have been added for all of the citations.


Wanted to point out, right off the bat, that RET has long been associated with medullary thyroid cancer, and Hirschprung's disease, since the early 90s (key figure being Chair of Surgery ironically at Wash U)


Yeah, but you could set this time frame, and it would be effective for that. In fact, maybe it should be a series like other annual issues... Maybe crowd-source a running list...?


Great summary - links to the papers would be even better!

Albert Vilella
Albert Vilella

Great compilation. I took the liberty of editing a bunch of wikipedia entries adding the relevant clinical details where absent:




Barrier to autointegration factor 1



Thrombopoietin receptor



RET proto-oncogene

MAX (gene)






Manuel P. Alonso
Manuel P. Alonso

Congratulations for your excellent blog and for the article 'Disease-causing Mutations Discovered by NGS in 2011'.

With kind regards.

Manuel Perez-Alonso, Prof.

Department of Genetics

University of Valencia


Dan Koboldt
Dan Koboldt

Thanks, Mary! I had the same thought. My only concern is that sequencing-enabled discoveries are already outstripping the pace at which I could write a review article about them. C'est la vie.


This is a nice summary. You should turn it into a paper.