Disease-causing Mutations Discovered by NGS

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.

Myopathies

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).

Myopathies
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.
ALMS1 IQCB1 CNGA3 MYO7A	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.

References
Shendure, J. (2011). Next-generation human genetics Genome Biology, 12 (9) DOI: 10.1186/gb-2011-12-9-408

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This entry was posted on Thursday, December 29th, 2011 at 12:04 pm by Dan Koboldt + and is filed under Human Genetics, Uncategorized. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

11 comments

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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)

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.

Thanks,

Joanne

Here's another for you:

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

PMID: 21901792

Dan Koboldt

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

Fred

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)

Mary

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...?

Neil

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

Albert Vilella

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

RRM2B

MRPL3

DYNC1H1

Barrier to autointegration factor 1

AFG3L2

FA2H

Thrombopoietin receptor

GATA2

MTHFD1

RET proto-oncogene

MAX (gene)

SLC16A2

SHROOM3

WDR62

KIF22

SMOC2

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

Spain

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.