Research in Microtia and External Ear Malformations

Roland D. Eavey, M.D., S.M.

Professor of Otology and Laryngology, Harvard Medical School; Director, Pediatric Otolaryngology Service, Massachusetts Eye and Ear Infirmary

Research in microtia and aural atresia

Lab: Seidman Laboratory,

Department of Genetics, Harvard Medical School

77 Avenue Louis Pasteur, NRB room 256

Boston, Massachusetts. 02115

PIs: Christine E. Seidman, M.D. and Jonathan G. Seidman, Ph.D.

 

Contact Information:

Co-PI: Roland D. Eavey, MD, SM

Professor of Otology and Laryngology, Harvard Medical School

Ex-Director, Pediatric Otolaryngology Service, Massachusetts Eye and Ear Infirmary (to 2009)

Current Chair of the Department of Otolaryngology and Director of Bill Wilkerson Center, Vanderbilt University

roland.d.eavey@vanderbilt.edu

ron.eavey@vanderbilt.edu

 

Current Research Fellows:

Maria Alexandra Artunduaga, M.D.

martunduaga@genetics.med.harvad.edu

 

Past Research Fellows:

Maria de Lourdes Quintanilla-Dieck, M.D. – PGY-1 Otolaryngology resident in Oregon health sciences university (OHSU)

Yamileht Nicolau, M.D. –PGY-3 Otolaryngology resident in University of California in San Diego (UCSD)

Thomas Tamura, M.D. – PGY-3 Otolaryngology resident in University of Vermont

                         

 

Picture 1. Dr. Eavey with MEEI research fellows Maria Alexandra Artunduaga and Maria de Lourdes Quintanilla-Dieck. Picture 2. In 2008,  Dr. Quintanilla-Dieck was awarded with a first prize travel grant for her work about music-induced hearing loss. Picture 3. Dr. Artunduaga
received the first prize William P. Potsic award 2009 in basic science for her genetic study with twins.

The primary goal of our research is to understand the molecular genetic basis of microtia (a congenital external ear malformation). A new and exciting approach to genetics research is through genome-wide association studies, which have led to the discovery of regions on the genome that contribute to complex diseases. We are currently in the process of running an association study (using the Affymetrix 6.0 chip) for microtia, using over 100 South American trios comprised of one proband (affected child) and two unaffected parents. We are also conducting a classical twins study, for which we have recruited 35 twin pairs, in the hopes that this will shed further light on genetic vs. environmental contributions to the etiology of microtia. In genetics research, it has been found that some malformations are due to somatic mutations, which occur after fertilization and only in certain cells, leading to genetic defects in the body parts that develop from these cells. To further explore the possibility that somatic mutations may cause external ear malformations, we wish to carry out a project involved in RNA expression analysis, comparing ear cartilage from microtia patients to cartilage from well-developed ears. Using these multiple approaches to microtia research, we hope to achieve a better understanding of the pathogenesis of this malformation.

  

 

 

 

Figure 1. Microtia is a congenital malformation of the external ear that can occur in different degrees of severity as shown from left (mild microtia) to right (severe or anotia)

 
                      

Figure 2. ^Twin pairs classified using all ear malformations (e.g. skin tags, clefts, microtia) and only microtia were stratified by zygosity. Zygosity was confirmed using 17 high-heterozygosity microsatellite markers. P-values were calculated for association between zygosity and outcome using logistic regression models, adjusted for correlation among pairs from the same family. *Abbreviations: OR, Odds Ratio; CI=Confidence intervals

Dr Eavey’s publications with collaborators in the Seidman laboratory:

Artunduaga MA, Quintanilla-Dieck Mde L, Greenway S, Betensky R, Nicolau Y, Hamdan U, Jarrin P, Osorno G, Brent B, Eavey R, Seidman C, Seidman J.G. A classic twin study of external ear malformations, including microtia. NEJM. 2009 Sept 17;361(12):1216-1218

 

Greenway SC, Pereira AC, Lin JC, DePalma SR, Israel SJ, Mesquita SM, Ergul E, Conta JH, Korn JM, McCarroll SA, Gorham JM, Gabriel S, Altshuler DM, Quintanilla-Dieck Mde L, Artunduaga MA, Eavey RD, Plenge RM, Shadick NA, Weinblatt ME, De Jager PL, Hafler DA, Breitbart RE, Seidman JG, Seidman CE.De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet. 2009 Aug;41(8):931-5.

 

Depreux FF, Darrow K, Conner DA, Eavey RD, Liberman MC, Seidman CE, Seidman JG. Eya4-deficient mice are a model for heritable otitis media. J Clin Invest. 2008 Feb;118(2):651-8.

 

Keogh IJ, Troulis MJ, Monroy AA, Eavey RD, Kaban LB. Isolated microtia as a marker for unsuspected hemifacial microsomia. Arch Otolaryngol Head Neck Surg. 2007 Oct;133(10):997-1001.

 

Hinson JT, Fantin VR, Schönberger J, Breivik N, Siem G, McDonough B, Sharma P, Keogh I, Godinho R, Santos F, Esparza A, Nicolau Y, Selvaag E, Cohen BH, Hoppel CL, Tranebjaerg L, Eavey RD, Seidman JG, Seidman CE. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N Engl J Med. 2007 Feb 22;356(8):809-19.

 

Keogh IJ, Godinho RN, Wu TP, Diaz de Palacios AM, Palacios N, Bello de Alford M, De Almada MI, MarPalacios N, Vazquez A, Mattei R, Seidman C, Seidman J, Eavey RD. Clinical and genetic linkage analysis of a large Venezuelan kindred with Usher syndrome. Int J Pediatr Otorhinolaryngol. 2004 Aug;68(8):1063-8.

 

Eavey RD, Manolis EN, Lubianca J, Merchant S, Seidman JG, Seidman C. Mutations in COCH (formerly Coch5b2) cause DFNA9. Adv Otorhinolaryngol. 2000;56:101 2.

 

Schönberger J, Levy H, Grünig E, Sangwatanaroj S, Fatkin D, MacRae C, Stäcker H, Halpin C, Eavey R, Philbin EF, Katus H, Seidman JG, Seidman CE. Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24.Circulation. 2000 Apr 18;101(15):1812-8.

 

Manolis EN, Eavey RD, Sangwatanaroj S, Halpin C, Rosenbaum S, Watkins H, Jarcho J, Seidman CE, Seidman JG. Hereditary postlingual sensorineural hearing loss mapping to chromosome Xq21.Am J Otol. 1999 Sep;20(5):621-6.

 

Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB Jr, Miyamoto RT, Linthicum FH Jr, Lubianca Neto JF, Hudspeth AJ, Seidman CE, Morton CC, Seidman JG. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction.

Nat Genet. 1998 Nov;20(3):299-303.

 

Lubianca Neto JF, Lu L, Eavey RD, Flores MA, Caldera RM, Sangwatanaroj S, Schott JJ, McDonough B, Santos JI, Seidman CE, Seidman JG. The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36. Am J Hum Genet. 1998 May;62(5):1107-12.

 

Manolis EN, Yandavi N, Nadol JB Jr, Eavey RD, McKenna M, Rosenbaum S, Khetarpal U, Halpin C, Merchant SN, Duyk GM, MacRae C, Seidman CE, Seidman JG.

A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13. Hum Mol Genet. 1996 Jul;5(7):1047-50.

 

Links:

Seidman Laboratory

Maria Alexandra Artunduaga, M.D.