Damaging variants in FOXI3 cause microtia and craniofacial microsomia.
Craniofacial microsomia
Ectoderm
FOXI3
Microtia
Neural crest
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
01
07
2022
revised:
11
09
2022
accepted:
12
09
2022
pubmed:
20
10
2022
medline:
11
1
2023
entrez:
19
10
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 36260083
pii: S1098-3600(22)00941-8
doi: 10.1016/j.gim.2022.09.005
pmc: PMC9885525
mid: NIHMS1864558
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
143-150Subventions
Organisme : NIDCD NIH HHS
ID : R00 DC011282
Pays : United States
Organisme : NIDCR NIH HHS
ID : U01 DE025862
Pays : United States
Organisme : NIDCR NIH HHS
ID : RC1 DE020270
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of Interest The authors declare no conflicts of interest.
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