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00925njm 22002777a 4500 dc Palencia-Campos, Adrián author Martinez-Fernandez, Maria Luisa author Altunoglu, Umut author Soto-Bielicka, Patricia author Torres, Antonio author Marín, Purificación author Aller, Elena author Şentürk, Leyli author Berköz, Ömer author Yıldıran, Mehmet author Kayserili, Hülya author Gil-Camarero, Elena author Colli-Lista, Gloria author Sanchís-Calvo, Amparo author Carretero, Alba author ECEMC Working Group on Polydactyly author Guillén-Navarro, Encarna author López-González, Vanesa author Ballesta-Martínez, María author Rosell, Jordi author Aglan, Mona S author Temtamy, Samia author Otaify, Ghada A author Cuevas Catalina, María Lourdes author Torres-Saavedra, María-Nieves author Nevado, Julián author Tenorio, Jair author Lapunzina, Pablo author Bermejo-Sanchez, Eva author Ruiz-Pérez, Víctor L author 2020-01 Postaxial 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. Palencia-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. 10.1002/humu.23921 1098-1004 1059-7794 Human mutation. Mutation in brief 31549748 https://hdl.handle.net/20.500.12105/26037 GLI1 Hedgehog signaling Incomplete penetrance Limb development Postaxial polydactyly A/B Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B