Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B

Palencia-Campos, AdriánMartinez-Fernandez, Maria LuisaAltunoglu, UmutSoto-Bielicka, PatriciaTorres, AntonioMarín, PurificaciónAller, ElenaŞentürk, LeyliBerköz, ÖmerYıldıran, MehmetKayserili, HülyaGil-Camarero, ElenaColli-Lista, GloriaSanchís-Calvo, AmparoCarretero, AlbaECEMC Working Group on PolydactylyGuillén-Navarro, EncarnaLópez-González, VanesaBallesta-Martínez, MaríaRosell, JordiAglan, Mona STemtamy, SamiaOtaify, Ghada ACuevas Catalina, María LourdesTorres-Saavedra, María-NievesNevado, JuliánTenorio, JairLapunzina, PabloBermejo-Sanchez, EvaRuiz-Pérez, Víctor L2025-01-162025-01-162020-01Palencia-Campos A, Martínez-Fernández ML, Altunoglu U, Soto-Bielicka P, Torres A, Marín P, Aller E, Şentürk L, Berköz Ö, Yıldıran M, Kayserili H, Gil-Camarero E, Colli-Lista G, Sanchís-Calvo A, Carretero A; ECEMC Working Group on Polydactyly; Guillén-Navarro E, López-González V, Ballesta-Martínez M, Rosell J, Aglan MS, Temtamy S, Otaify GA, Cuevas-Catalina L, Torres-Saavedra MN, Nevado J, Tenorio J, Lapunzina P, Bermejo-Sánchez E, Ruiz-Pérez VL. Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B. Hum Mutat. 2020 Jan;41(1):265-276.1059-7794https://hdl.handle.net/20.500.12105/26037Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/GLI1Hedgehog signalingIncomplete penetranceLimb developmentPostaxial polydactyly A/BAllelesAmino Acid SubstitutionFemaleFibroblastsFingersGene ExpressionGenes, DominantGenes, ReporterGenetic Association StudiesGenetic Predisposition to DiseaseGenetic VariationGenotypeHeterozygoteHumansInfantInfant, NewbornMalePedigreePhenotypePolydactylyPolymorphism, Single NucleotideSequence Analysis, DNAToesZinc Finger Protein GLI1Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/BAttribution-NonCommercial-NoDerivatives 4.0 International31549748411265-27610.1002/humu.239211098-1004Human mutation. Mutation in briefopen access