Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations.

Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell­derived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

Status of trauma quality improvement programs in the Andean region: What foundation do we have to build on.

INTRODUCTION: Trauma quality improvement (QI) programs have been shown to improve outcomes and decrease cost. These are high priorities in low- and middle-income countries (LMICs), where 2,000,000 deaths due to survivable injuries occur each year. We sought to define areas for improvement in trauma QI programs in four LMICs. METHODS: We conducted a survey among trauma care providers in four Andean middle-income countries: Bolivia, Colombia, Ecuador, and Peru. RESULTS: 336 physicians, medical students, nurses, administrators and paramedical professionals responded to the cross-sectional survey with a response rate greater than 90% in all included countries except Bolivia, where the response rate was 14%. Eighty-seven percent of respondents reported morbidity and mortality (M&M) conferences occur at their hospital. Conferences were often reported as infrequent - 45% occurred less than every three months and poorly attended - 63% had five or fewer staff physicians present. Only 23% of conferences had standardized selection criteria, most lacked documentation - notes were taken at only 35% of conferences. Importantly, only 13% of participants indicated that discussions were routinely followed-up with any sort of corrective action. Multivariable analysis revealed the presence of standardized case selection criteria (OR 3.48, 95% CI 1.16-10.46), written documentation of the M&M conferences (OR 5.73, 95% CI 1.73-19.06), and a clear plan for follow-up (OR 4.80, 95% CI 1.59-14.50) to be associated with effective M&M conferences. Twenty-two percent of respondents worked at hospitals with a trauma registry. Fifty-two percent worked at institutions where autopsies were conducted, but only 32% of those reported the autopsy results to ever be used to improve hospital practice. CONCLUSIONS: M&M conferences are frequently practiced in the Andean region of Latin America but often lack methodologic rigor and thus effectiveness. Next steps in the maturation of QI programs include optimizing use of data from autopsies and registries, and systematic follow-up of M&M conferences with corrective action to ensure that these activities result in appreciable changes in clinical care.

HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.