Heterozygous pathogenic variants inGLI1are a common finding in isolated postaxial polydactyly A/B

Abstract

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.

A Novel Homozygous Missense Mutation in the Zinc Finger DNA Binding Domain of GLI1 Causes Recessive Post-Axial Polydactyly

“…GLI1 (GLI Family Zinc Finger 1) is a member of the Kruppel family of zinc finger proteins. Variants in GLI1 gene have been associated with polydactyly PAPA8 and PPD type I (Ullah et al, 2019(a); Palencia-Campos et al, 2020). In the present investigation, using WES followed by bi-directional Sanger sequencing, we have identified a novel biallelic missense 3) and is highly conserved across multiple species (Figure 1I).…”

“…Close-up of Leu247 and Adenine A-7 is provided in the inset. phenotypes (Ullah et al, 2019(a); Palencia-Campos et al, 2020). Ullah I. et al (2019) reported a Pakistani family segregating PPD in recessive fashion and having a missense variant (c.1517 T > A; p. Leu506Gln) in GLI1 gene.…”

“…No. 4484177) (Palencia-Campos et al, 2020). Finally, 25 µl (∼100 pM) of the DNA library was transferred to position A of the reagent cartridge (Zhang et al, 2017).…”

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

“…The same picture emerges when we examine missense variants in other GLI‐family members. Regarding GLI1 , variants segregating with dominant nonsyndromic A/B‐type PAP were recently reported, and all the missense variants (6 in all) were in the Zn‐fingers of GLI1 (Palencia‐Campos et al, 2020; Yousaf et al, 2020). Variable digital and other abnormalities in a large family segregated with a missense GLI3 variant Cys609Tyr in Zn‐finger number 5 (Crapster et al, 2017), and the same Zn‐finger was affected in a four‐generation family with Greig cephalopolysyndactyly syndrome segregating with a GLI3 p.(Arg625Trp) variant (Debeer et al, 2003).…”

Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes

“…Homozygous LOF mutations in GLI1 cause postaxial polydactyly without any other symptoms; Polydactyly, postaxial, type A8; PAPA8 #618123 [ 114 ]. Also, heterozygous LOF mutations of GLI1 are a common finding in isolated postaxial polydactyly A/B [ 115 ]. The absence of craniofacial and central nervous system malformations may reflect the fact that GLI1 generally does not play as important a role in the SHH pathway for morphogenesis as GLI2 and GLI3.…”