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Osteogenesis imperfecta

The classic blue sclerae of a person with osteogenesis imperfecta

Classification and external resources

ICD-10 Q78.0(http://apps.who.int/classifications/icd10/browse/2015/en#/Q78.0)

ICD-9 756.51 (http://www.icd9data.com/getICD9Code.ashx?icd9=756.51)

DiseasesDB 9342 (http://www.diseasesdatabase.com/ddb9342.htm)

MedlinePlus 001573(http://www.nlm.nih.gov/medlineplus/ency/article/001573.htm)

eMedicine ped/1674 (http://www.emedicine.com/ped/topic1674.htm)

Patient UK Osteogenesis imperfecta(http://www.patient.co.uk/doctor/osteogenesis-imperfecta)

MeSH D010013 (https://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?field=uid&term=D010013)

Osteogenesis imperfectaFrom Wikipedia, the free encyclopedia

Osteogenesis imperfecta (OI),also known as brittle bonedisease or Lobsteinsyndrome,[1] is a congenitalbone disorder characterized bybrittle bones that are prone tofracture. People with OI are bornwith defective connective tissue,or without the ability to make it,usually because of a deficiencyof type I collagen.[2] Eight typesof OI can be distinguished. Mostcases are caused by mutations inthe COL1A1 and COL1A2 genes.

Diagnosis of OI is based on theclinical features and may beconfirmed by collagen or DNAtesting. There is no cure for OI.Treatment is aimed at increasingoverall bone strength to preventfracture and maintain mobility.OI occurs in about one per20,000 live births.

Contents

1 Classification1.1 Type I1.2 Type II1.3 Type III1.4 Type IV1.5 Type V1.6 Type VI1.7 Type VII1.8 Type VIII1.9 Other genes

2 Pathophysiology

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3 Diagnosis4 Treatment

4.1Bisphosphonates4.2 Surgery4.3 Physiotherapy4.4 Physical aids

5 History6 Epidemiology7 Noted cases

7.1 Disputed8 In media9 Other animals10 See also11 References12 External links

ClassificationOf the eight different types of OI, type I is the most common, though the symptoms vary from person toperson.

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Blue sclera in osteogenesisimperfecta.

Type Description Gene OMIM Mode ofinheritance

I mildNullCOL1A1allele

166240(https://omim.org/entry/166240)(IA), 166200(https://omim.org/entry/166200)(IB)

autosomaldominant,60% denovo[3]

II severe and usually lethal in theperinatal period

COL1A1,COL1A2,

166210(https://omim.org/entry/166210)(IIA), 610854(https://omim.org/entry/610854)(IIB)

autosomaldominant,~100% denovo[3]

III considered progressive anddeforming

COL1A1,COL1A2

259420(https://omim.org/entry/259420)

autosomaldominant,~100% denovo[3]

IV deforming, but with normalsclerae most of the time

COL1A1,COL1A2

166220(https://omim.org/entry/166220)

autosomaldominant,60% denovo[3]

Vshares the same clinical featuresof IV, but has unique histologicfindings ("mesh-like")

IFITM5 610967(https://omim.org/entry/610967)

autosomaldominant[3][4]

VIshares the same clinical featuresof IV, but has unique histologicfindings ("fish scale")

SERPINF1 610968(https://omim.org/entry/610968)

autosomalrecessive[3]

VII associated with cartilageassociated protein CRTAP 610682

(https://omim.org/entry/610682)autosomalrecessive[3]

VIII severe to lethal, associated withthe protein leprecan LEPRE1 610915

(https://omim.org/entry/610915)autosomalrecessive

Type I

Collagen is of normal quality but is produced in insufficientquantities:

Bones fracture easilySlight spinal curvatureLoose jointsPoor muscle toneDiscoloration of the sclera (whites of the eyes), usually givingthem a blue-gray color. The blue-gray color of the sclera isdue to the underlying choroidal veins which show through.This is due to the sclera being thinner than normal because ofthe defective Type I collagen not forming correctly.

Early loss of hearing in some children[5]

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Slight protrusion of the eyes

IA and IB are defined to be distinguished by the absence/presence of dentinogenesis imperfecta(characterized by opalescent teeth; absent in IA, present in IB). Life expectancy is slightly reducedcompared to the general population due to the possibility of fatal bone fractures and complications related toOI Type I such as basilar invagination.

Type II

Collagen is not of a sufficient quality or quantity

Most cases die within the first year of life due to respiratory failure or intracerebral hemorrhageSevere respiratory problems due to underdeveloped lungsSevere bone deformity and small stature

Type II can be further subclassified into groups A, B, and C, which are distinguished by radiographicevaluation of the long bones and ribs. Type IIA demonstrates broad and short long bones with broad andbeaded ribs. Type IIB demonstrates broad and short long bones with thin ribs that have little or no beading.Type IIC demonstrates thin and longer long bones with thin and beaded ribs.

Type III

Collagen improperly formed, enough collagen is made but it is defective

Bones fracture easily, sometimes even before birthBone deformity, often severeRespiratory problems possibleShort stature, spinal curvature and sometimes barrel-shaped rib cage

Triangular face[6]

Loose joints(double jointed)Poor muscle tone in arms and legsDiscolouration of the sclera (the 'whites' of the eyes are blue)Early loss of hearing possible

Type III is distinguished among the other classifications as being the "progressive deforming" type, whereina neonate presents with mild symptoms at birth and develops the aforementioned symptoms throughout life.Lifespans may be normal, albeit with severe physical handicapping.

Type IV

Collagen quantity is sufficient but is not of a high enough quality

Bones fracture easily, especially before pubertyShort stature, spinal curvature and barrel-shaped rib cage

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OI Type V in anadult

OI Type V in achild

Bone deformity is mild to moderateEarly loss of hearing

Similar to Type I, Type IV can be further subclassified into types IVA and IVB characterized by absence(IVA) or presence (IVB) of dentinogenesis imperfecta.

Type V

Having the same clinical features as Type IV, it is distinguished histologically by"mesh-like" bone appearance. Further characterized by the "V triad" consisting of a)radio-opaque band adjacent to growth plates, b) hypertrophic calluses at fracture sites,and c) calcification of the radio-ulnar interosseous membrane.[7]

OI Type V leads to calcification of the membrane between the two forearm bones,making it difficult to turn the wrist. Another symptom is abnormally large amounts ofrepair tissue (hyperplasic callus) at the site of fractures. Other features of this conditioninclude radial head dislocation, long bone bowing and mixed hearing loss.

At least some cases of this type are caused by mutations in the interferon inducedtransmembrane protein 5 (IFITM5) gene.[4]

Type VI

With the same clinical features as Type IV, it is distinguished histologically by "fish-scale" bone appearance. Type VI has recently been found to be caused by a loss offunction mutation in the SERPINF1 gene. SERPINF1, a member of the serpin family, isalso known as pigment epithelium derived factor (PEDF), the most powerfulendogenous antiangiogenic factor in mammals.

Type VII

In 2006, a recessive form called "Type VII" was discovered (phenotype severe to lethal). Thus far it seemsto be limited to a First Nations people in Quebec.[8] Mutations in the gene CRTAP causes this type.[9]

Type VIII

OI caused by mutation in the gene LEPRE1 is classified as type VIII.[9]

Other genes

A family with recessive osteogenesis imperfecta has been reported to have a mutation in the TMEM38Bgene on chromosome 9.[10] This gene encodes TRIC-B, a component of TRIC, a monovalent cation-specificchannel involved in calcium release from intracellular stores.

It is extremely likely that there are other genes associated with this disease that have yet to be reported.

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PathophysiologyPeople with OI are born with defective connective tissue, or without the ability to make it, usually becauseof a deficiency of Type-I collagen.[2] This deficiency arises from an amino acid substitution of glycine tobulkier amino acids in the collagen triple helix structure. The larger amino acid side-chains create sterichindrance that creates a bulge in the collagen complex, which in turn influences both the molecularnanomechanics and the interaction between molecules, which are both compromised.[11] As a result, thebody may respond by hydrolyzing the improper collagen structure. If the body does not destroy theimproper collagen, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone isaltered, causing brittleness.[12] Another suggested disease mechanism is that the stress state within collagenfibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrilseven at moderate loads as the homogeneous stress state found in healthy collagen fibrils is lost.[11] Theserecent works suggest that OI must be understood as a multi-scale phenomenon, which involves mechanismsat the genetic, nano-, micro- and macro-level of tissues.

As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen.Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. In the past several years,there has been the identification of autosomal recessive forms.[13] Most people with OI receive it from aparent but in 35% of cases it is an individual (de novo or "sporadic") mutation.

DiagnosisThere is no definitive test for OI. The diagnosis is usually suggested by the occurrence of bone fractureswith little trauma and the presence of other clinical features. Skin biopsy can be performed to determine thestructure and quantity of type I collagen. DNA testing can confirm the diagnosis, however it cannot excludeit, because not all mutations causing OI are known and/or tested for. OI type II is often diagnosed byultrasound during pregnancy, where already multiple fractures and other characteristic features may bepresent. Relative to control, OI cortical bone shows increased porosity, canal diameter, and connectivity inmicro-computed tomography.[14]

An important differential diagnosis of OI is child abuse, as both may present with multiple fractures invarious stages of healing. Differentiating them can be difficult, especially when no other characteristicfeatures of OI are present. Other differential diagnoses include rickets, osteomalacia, and other rare skeletalsyndromes.

TreatmentThere is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture andmaintain mobility. Bisphosphonates can increase bone mass, and reduce bone pain and fracture. In severecases, bones are surgically corrected, and rods are placed inside the bones, particularly to enable infants tolearn to walk.

Bone infections are treated as and when they occur with the appropriate antibiotics and antiseptics.

Bisphosphonates

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In 1998, a clinical trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate whichhad previously been used in adults to treat osteoporosis. In severe OI, pamidronate reduced bone pain,prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the numberof long-bone fractures.[15]

Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, andintravenous bisphosphonates are generally more effective, although this is under study. Some studies havefound oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate,equivalent.[16] In a trial of children with mild OI, oral risedronate increased bone mineral densities, andreduced nonvertebral fractures. However, it did not decrease new vertebral fractures.[17][18]

Bisphosphonates are less effective for OI in adults.[19]

Surgery

Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed byHarold A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During the late 1940s, Sofield, Chiefof Staff at Shriners Hospitals in Chicago, worked there with large numbers of children with OI andexperimented with various methods to strengthen the bones in these children.[20] In 1959, with Edward A.Miller, MD, Sofield wrote a seminal article describing a solution that seemed radical at the time: theplacement of stainless steel rods into the intramedullary canals of the long bones to stabilize and strengthenthem. His treatment proved extremely useful in the rehabilitation and prevention of fractures; it was adoptedthroughout the world and still forms the basis for orthopedic treatment of OI.

Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operationmore complex in OI patients. Surgery for basilar impressions can be carried out if pressure being exerted onthe spinal cord and brain stem is causing neurological problems.

Physiotherapy

Physiotherapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing therisk of fracture. This often involves hydrotherapy and the use of support cushions to improve posture.Individuals are encouraged to change positions regularly throughout the day to balance the muscles beingused and the bones under pressure.

Children often develop a fear of trying new ways of moving due to movement being associated with pain.This can make physiotherapy difficult to administer to young children.

Physical aids

With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, and/or modifications to thehome, many individuals with OI can obtain a significant degree of autonomy.

History

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The condition, or types of it, has had various other names over the years and in different nations. Amongsome of the most common alternatives are Ekman-Lobstein syndrome, Vrolik syndrome, and thecolloquial glass-bone disease. The name osteogenesis imperfecta dates to at least 1895[21] and has beenthe usual medical term in the 20th century to present. The current four type system began with Sillence in1979.[22] An older system deemed less severe types "osteogenesis imperfecta tarda" while more severeforms were deemed "osteogenesis imperfecta congenita."[23] As this did not differentiate well, and all formsare congenital, this has since fallen out of favour.

The condition has been found in an ancient Egyptian mummy from 1000 BC. The Norse king Ivar theBoneless may have had this condition, as well. The earliest studies of it began in 1788 with the Swede OlofJakob Ekman. He described the condition in his doctoral thesis and mentioned cases of it going back to1678. In 1831, Edmund Axmann described it in himself and two brothers. Jean Lobstein dealt with it inadults in 1833. Willem Vrolik did work on the condition in the 1850s. The idea that the adult and newbornforms were the same came in 1897 with Martin Benno Schmidt.[24]

EpidemiologyIn the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 livebirths.[25] An estimated 20,000 to 50,000 people are affected by OI in the United States.

Frequency is approximately the same across groups, but for unknown reasons, the Shona and Ndebele ofZimbabwe seem to have a higher proportion of Type III to Type I than other groups.[26] However, a similarpattern was found in segments of the Nigerian and South African populations. In these varied cases, the totalnumber of OIs of all four types was roughly the same as any other ethnicity.

Noted cases

American actors Michael J. Anderson,[27][28] Tarah Lynne Schaeffer (Sesame Street)[29] and Atticus

Shaffer[30][31][32]

Leo Beuerman, subject of the documentary Leo Beuerman, which was nominated for the Academy

Award for Best Documentary (Short Subject).[33]

British actors Julie Fernandez,[34] Nabil Shaban,[35] and Kerry Ingram.[36]

Canadian actor Rick Howland[37] who is known for Lost Girl.

Danish actress and singer Pernille Vallentin.[38]

German philologist, actor, and founder of Die Deutsche Gesellschaft für Osteogenesis Imperfecta,

Peter Radtke.[39]

British peer Nicky Chapman, Baroness Chapman[40]

Randy Guss, drummer for Toad the Wet Sprocket[41][42]

Hip-hop artist and producer Kalyn Heffernan[43]

American Olympic bronze medalist coxswain Doug Herland[44]

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British poet Christopher Hewitt,[45] namesake of the Christopher Hewitt Award.

Paralympic gold and bronze medalist in sledge hockey, Taylor Lipsett[46][47]

Paralympic bronze medalist in Wheelchair tennis at the 2012 Summer Paralympics, Jordanne

Whiley.[48][49]

Paralympic multiple medalist in shooting Josef Neumaier de:Josef Neumaier[50]

Zimbabwean marimba player Energy Maburutse[51][52]

Japanese countertenor singer Yoshikazu Mera

Jazz pianist Michel Petrucciani[53]

Parsi playwright Firdaus Kanga[54]

Guinness World Records' shortest man He Pingping[55]

Motivational speaker Sean Stephenson[56]

French speaking poet and novelist Philippe Rahmy,[57] Type IA

Australian reality TV personality Quentin Kenihan[58]

Australian comedian and journalist Stella Young.[59]

Lead singer of the Australian alternative rock group The White Room, Marc Collis[60]

Freyja Haraldsdottir, member of the Icelandic Constitutional Assembly of 2010.[61][62][63]

Italian journalist Franco Bomprezzi.[64]

Disputed

French artist Henri de Toulouse-Lautrec.[65] He was never diagnosed, and recent theories suggest that

he had a mild form of osteopetrosis instead.[66] Maroteaux and Lamy have suggested pyknodysostosisas the explanation.

Viking invader of England, Ivar the Boneless: There is notable speculation about his physicalcondition; but objective diagnosis is not possible since his skeleton was exhumed and burnt 200 years

after his death by William the Conquerer.[67]

In mediaFigures in film, television, video games and novels depicted as having osteogenesis imperfecta include:

(2013) Robbie Novak a.k.a. Kid President, a motivational speaker and YouTube personality, suffers

from the disorder.[68] He often comments on his own ability to overcome it.[69]

Other animals

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In dogs, OI is an autosomal-recessive condition. In Golden Retrievers, it is caused by a mutation in theCOL1A1, and in Beagles, the COL1A2. A separate mutation in the SERPINH1 gene has been found to causethe condition in Dachshunds.[70] Several mouse models of OI have been described, whereby the abnormalgait 2 (AGA2) mouse line exhibits severe skeletal[71] and cardio-pulmonary[72] phenotypes due to acarboxy-terminus mutation in the COL1A1 gene in the mouse.

See also

Brittle Bone Society

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(10th ed.). Saunders. Page 517. ISBN 0-7216-2921-0.2. Rauch F, Glorieux FH (2004). "Osteogenesis imperfecta". Lancet 363 (9418): 1377–85. doi:10.1016/S0140-

6736(04)16051-0 (https://dx.doi.org/10.1016%2FS0140-6736%2804%2916051-0). PMID 15110498(https://www.ncbi.nlm.nih.gov/pubmed/15110498).

3. Steiner RD, Pepin MG, Byers PH, Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP (January 28, 2005)."Osteogenesis Imperfecta" (http://www.ncbi.nlm.nih.gov/books/NBK1295/). PMID 20301472(https://www.ncbi.nlm.nih.gov/pubmed/20301472). Retrieved 26 March 2012.

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10. Volodarsky M, Markus B, Cohen I, Staretz-Chacham O, Flusser H, Landau D, Shelef I, Langer Y, Birk OS(2013) A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. HumMutat doi:10.1002/humu.22274 (https://dx.doi.org/10.1002%2Fhumu.22274)

11. Gautieri A, Uzel S, Vesentini S, Redaelli A, Buehler MJ (2009). "Molecular and mesoscale disease mechanismsof Osteogenesis Imperfecta" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718154). Biophysical Journal 97(3): 857–865. doi:10.1016/j.bpj.2009.04.059 (https://dx.doi.org/10.1016%2Fj.bpj.2009.04.059). PMC 2718154(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718154). PMID 19651044(https://www.ncbi.nlm.nih.gov/pubmed/19651044).

12. "Osteogenesis Imperfecta Foundation: Fast Facts" (http://www.oif.org/site/PageServer?pagename=FastFacts).Retrieved 2007-07-05.

13. Drögemüller C, Becker D, Brunner A, Haase B, Kircher P, Seeliger F, Fehr M, Baumann U, Lindblad-Toh K,Leeb T (2009). Barsh, Gregory S, ed. "A Missense Mutation in the SERPINH1 Gene in Dachshunds withOsteogenesis Imperfecta" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708911). PLoS Genetics 5 (7):e1000579. doi:10.1371/journal.pgen.1000579 (https://dx.doi.org/10.1371%2Fjournal.pgen.1000579).PMC 2708911 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708911). PMID 19629171(https://www.ncbi.nlm.nih.gov/pubmed/19629171).

14. http://proceedings.spiedigitallibrary.org/proceeding.aspx?articleid=167462515. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R (1998). "Cyclic administration of

pamidronate in children with severe osteogenesis imperfecta". N. Engl. J. Med. 339 (14): 947–52.doi:10.1056/NEJM199810013391402 (https://dx.doi.org/10.1056%2FNEJM199810013391402). PMID 9753709(https://www.ncbi.nlm.nih.gov/pubmed/9753709).Free full text

16. DiMeglio LA, Peacock M (2006). "Two-year clinical trial of oral alendronate versus intravenous pamidronate inchildren with osteogenesis imperfecta". J. Bone Miner. Res. 21 (1): 132–40. doi:10.1359/JBMR.051006(https://dx.doi.org/10.1359%2FJBMR.051006). PMID 16355282(https://www.ncbi.nlm.nih.gov/pubmed/16355282).

17. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial(http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961091-0/abstract), Lancet, 6 August2013

18. Oral bisphosphonates for paediatric osteogenesis imperfecta?(http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961531-7/fulltext) Lancet August 6,2013

19. Chevrel G, Schott AM, Fontanges E, Charrin JE, Lina-Granade G, Duboeuf F, Garnero P, Arlot M, Raynal C,Meunier PJ (2006). "Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-yearrandomized placebo-controlled trial". J. Bone Miner. Res. 21 (2): 300–6. doi:10.1359/JBMR.051015(https://dx.doi.org/10.1359%2FJBMR.051015). PMID 16418786(https://www.ncbi.nlm.nih.gov/pubmed/16418786).

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21. K. Buday, Beiträge zur Lehre von der Osteogenesis imperfecta (1895)

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22. Sillence DO, Senn A, Danks DM (1979). "Genetic heterogeneity in osteogenesis imperfecta"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1012733). J. Med. Genet. 16 (2): 101–16.doi:10.1136/jmg.16.2.101 (https://dx.doi.org/10.1136%2Fjmg.16.2.101). PMC 1012733(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1012733). PMID 458828(https://www.ncbi.nlm.nih.gov/pubmed/458828).

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24. synd/1743 (http://www.whonamedit.com/synd.cfm/1743.html) at Who Named It?25. eMedicine > Osteogenesis Imperfecta (http://emedicine.medscape.com/article/947588-overview) Author:

Horacio Plotkin. Updated: March 2, 201026. Viljoen D, Beighton P (1987). "Osteogenesis imperfecta type III: an ancient mutation in Africa?". Am. J. Med.

Genet. 27 (4): 907–12. doi:10.1002/ajmg.1320270417 (https://dx.doi.org/10.1002%2Fajmg.1320270417).PMID 3425600 (https://www.ncbi.nlm.nih.gov/pubmed/3425600).

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28. Dargis, Manohla (2005-02-07). "We're Sorry" (http://movies2.nytimes.com/gst/movies/filmography.html?p_id=1584&mod=bio). The New York Times. Retrieved 2010-05-20.

29. Williams Cook, Sally (17 January 1994). "Girl in wheelchair joins 'Sesame Street' cast"(http://news.google.com/newspapers?id=l-YyAAAAIBAJ&sjid=lwcGAAAAIBAJ&pg=3373,3068885&dq=sally+sesame-street&hl=en). The Free Lance-Star (Fredericksburg VA). p. B6. Retrieved 16 May 2011.

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Wikimedia Commons hasmedia related toOsteogenesis imperfecta.

External links

GeneReview/NCBI/NIH/UW entry on OsteogenesisImperfecta (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=oi)synd/1743 (http://www.whonamedit.com/synd.cfm/1743.html) at Who Named It?Osteogenesis Imperfecta Overview(http://www.niams.nih.gov/Health_Info/Bone/Osteogenesis_Imperfecta/default.asp)  NIHOsteoporosis and Related Bone Diseases ~ National Resource CenterType V Research (http://www.oif.org/site/PageServer?pagename=TypeVStudy), OsteogenesisImperfecta association

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Categories: Abnormalities of dermal fibrous and elastic tissue Skeletal disorders Collagen disease

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72. Thiele F, Cohrs CM, Flor A, Lisse TS, Przemeck GK, Horsch M, Schrewe A, Gailus-Durner V, Ivandic B, KatusHA, Wurst W, Reisenberg C, Chaney H, Fuchs H, Hans W, Beckers J, Marini JC, Hrabé de Angelis M. (Aug2012). "Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients arecaused by bone-independent mechanisms." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406754). Hum MolGenet. 21 (16): 3535–45. doi:10.1093/hmg/dds183 (https://dx.doi.org/10.1093%2Fhmg%2Fdds183).PMC 3406754 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406754). PMID 22589248(https://www.ncbi.nlm.nih.gov/pubmed/22589248).