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

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 t...

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Bibliographic Details
Authors: Palencia-Campos, Adrián, Martinez-Fernandez, Maria Luisa, Altunoglu, Umut, Soto-Bielicka, Patricia, Torres, Antonio, Marín, Purificación, Aller, Elena, Şentürk, Leyli, Berköz, Ömer, Yıldıran, Mehmet, Kayserili, Hülya, Gil-Camarero, Elena, Colli-Lista, Gloria, Sanchís-Calvo, Amparo, Carretero, Alba, ECEMC Working Group on Polydactyly, Guillén-Navarro, Encarna, López-González, Vanesa, Ballesta-Martínez, María, Rosell, Jordi, Aglan, Mona S, Temtamy, Samia, Otaify, Ghada A, Cuevas Catalina, María Lourdes, Torres-Saavedra, María-Nieves, Nevado, Julián, Tenorio, Jair, Lapunzina, Pablo, Bermejo-Sanchez, Eva, Ruiz-Pérez, Víctor L
Format: article
Publication Date:2020
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26037
Online Access:https://hdl.handle.net/20.500.12105/26037
Access Level:Open access
Keyword:GLI1
Hedgehog signaling
Incomplete penetrance
Limb development
Postaxial polydactyly A/B
Alleles
Amino Acid Substitution
Female
Fibroblasts
Fingers
Gene Expression
Genes, Dominant
Genes, Reporter
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genotype
Heterozygote
Humans
Infant
Infant, Newborn
Male
Pedigree
Phenotype
Polydactyly
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Toes
Zinc Finger Protein GLI1
Description
Summary: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.

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