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.

Haploinsufficiency of SF3B2 causes craniofacial microsomia.

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.

MYT1 role in the microtia-craniofacial microsomia spectrum.

BACKGROUND: Craniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, comprises a variable phenotype with the most common features including microtia and mandibular hypoplasia on one or both sides, in addition to lateral oral clefts, epibulbar dermoids, cardiac, vertebral, and renal abnormalities. The etiology of CFM is largely unknown. The MYT1 gene has been reported as a candidate based in mutations found in three unrelated individuals. Additional patients with mutations in this gene are required to establish its causality. We present two individuals with CFM that have rare variants in MYT1 contributing to better understand the genotype and phenotype associated with mutations in this gene. METHODS/RESULTS: We conducted genetic analysis using whole-exome and -genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants. Sanger sequencing was used to confirm these mutations. CONCLUSION: We identified two additional individuals with CFM who carry rare variants in MYT1, further supporting the presumptive role of this gene in the CFM spectrum.

Enzyme replacement therapy interruption in patients with Mucopolysaccharidoses: Recommendations for distinct scenarios in Latin America.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, leading to the progressive accumulation of glycosaminoglycans (GAGs) and the subsequent compromising of tissues and organ malfunction. Although incurable, most types of MPS can be treated with enzyme replacement therapy (ERT), an approach that has had positive effects on the natural clinical evolution and which impact has been extensively investigated. Unfortunately, to date, there is relatively little data regarding the effects of ERT interruption, especially in Latin America, where such interruption may be frequent due to a variety of issues (for instance, difficulties involving logistics, reimbursement and/or payment withdrawal). METHOD: A group of medical professionals from Latin America with experience in Genetics, Pediatrics and Neurology held an Advisory Board Meeting in the city of São Paulo, in October 2018, to discuss the issue of ERT interruptions in the region and recommendations health care professionals on how to deal with these interruptions and better assess the therapeutic effects of ERT. CONCLUSION: Recommendations provided by the experts may support physicians in dealing with the most common reasons for ERT interruptions in Latin America. Most importantly, recommendations for data collection at specific timepoints (at baseline, throughout the treatment and during the interruption period of ERT and after its resumption) can significantly improve the collection of real world evidence on the effects of ERT and its interruptions, supporting health care professionals and policy makers in the decision making regarding the provision of these therapies for MPS patients.