|Project Number:||1 X01 HL145690-01||Contact PI / Project Leader:||Seidman, Jonathan G|
|Title:||The Genetics of Microtia in Hispanic Populations||Awardee Organization:||Harvard Medical School|
DESCRIPTION (provided by applicant):
Microtia is a rare congenital deformity of the external ear, the pinna. The severity of microtia is variable and ranges from subtle deformities in the pinna to absence of the external ear. Microtia is often associated with closure of the external auditory ear canal causing significant hearing loss. Microtia can be an isolated, unilateral or bilateral malformation, or occur solely with ear canal deformities, or with additional craniofacial or syndromic manifestations. Our study of identical twins with microtia demonstrated a significant genetic contribution. The molecular pathogenesis for most microtia remains unknown. We propose to leverage our clinical acumen in diagnosis and treatment of microtia (R.E.), our relationship to the microtia community (M.T.) and our collected DNA samples from microtia patients to identify genetic variant(s) that contribute to this congenital malformation. Microtia prevalence is much higher among Native Americans and some Latin Americans (17 per 10000 Ecuadorian births) than among individuals of European-descent (0.6 -1.6 per 10,000 births). To capitalize on this epidemiologic data, we have recruited microtia cohorts from Latin America and the U.S, including clinical data and DNA samples. We propose whole genome sequence of existing samples from isolated cases, trios (proband and parents) and one large family we propose comprehensive genetic analyses to interrogate coding and non-coding sequence variants associated with microtia. We hypothesize that genetic variants that cause microtia and other less pathogenic conditions, which have relatively small impact on reproductive fitness, are likely to be tolerated and inherited, but cause malformations in only a fraction of variant carriers (i.e. reduced penetrance). We suggest that we have power to detect a variant that increases the relative risk of microtia by >2.5 (i.e. a penetrance of ~3%). We suggest that microtia likely reflects variants with low penetrance that impact genes that participate in the molecular pathways of ear development. Such variants may also contribute to other hearing and craniofacial malformations. We expect to harness the insights and reagents developed here to elucidate factors that impact the penetrance of variants. Because of the prevalence of microtia in Latin America there are microtia support groups in Mexico, Colombia, and Ecuador. We have formed alliances, through our collaborator Melissa Tumblin (Ear Community), with these microtia support groups. We anticipate that any associations detected in the preliminary whole genome sequence (WGS) cohort will be confirmed in a second cohort of microtia patients. We request that the Gabrielle-Miller Kids First program support WGS of 821 microtia subjects and their parents as follows: a) 200 microtia probands; b) 200 trios (proband and both parents) and c) 21 members of family 3Sz. PUBLIC HEALTH RELEVANCE: We request whole genome sequence of 821 Hispanic subjects who have at least one family member with microtia, or abnormal outer ear formation. There are 200 microtia probands without parents, and 200 microtia probands with parents (trios, n=400) and 21 from a large family with 6 cases of microtia. We expect that analysis of the WGS will identify a gene variant(s) that increases the risk of microtia in some Latin American populations by ~25 fold and will provide new insights into the development of the outer ear.