Novel heterozygous sequence variant in the GLI1 underlies postaxial polydactyly

Yousaf, Maryam; Ullah, Asmat; Azeem, Zahid; Majeed, Ayesha Isani; Memon, Muhammad Iqbal; Ghous, Tahseen; Basit, Sulman; Ahmad, Farooq

doi:10.1111/cga.12361

Cited by 7 publications

(3 citation statements)

References 14 publications

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“…In our study, central polydactyly was observed only in 1 patient (patient 3). It is known that preaxial and postaxial polydactyly is a feature of CFNS, but central polydactyly, which is a rarely observed duplication of any of the central 3 digits (second, third and fourth) [Yousaf et al, 2020], has not been previously reported in this syndrome. Central polydactyly is a feature found in different syndromes including Orofaciodigital syndrome, Bardet Biedl syndrome, McKusick Kaufmann syndrome, and Synpolydactyly syndromes [Schaefer et al, 2013].…”

Section: Discussionmentioning

confidence: 91%

Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel EFNB1 Gene Mutation

Gürsoy¹,

Hazan²,

Öztürk³

et al. 2021

Mol Syndromol

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Craniofrontonasal syndrome (CFNS) is a rare X-linked genetic disorder which is characterized by coronal synostosis, widely spaced eyes, a central nasal groove, and various skeletal anomalies. Mutations in the EFNB1 gene in Xq13.1 are responsible for familial and sporadic cases. In the present study, we aimed to evaluate the clinical characteristics and molecular results of 4 patients with CFNS. Genomic DNA was extracted from the peripheral blood lymphocytes of all patients and their parents, and Sanger sequencing of the EFNB1 gene was performed. A novel EFNB1 gene mutation (c.65delG; p.Cys22SerfsTer24) was detected in a newborn who had only dysmorphic facial features and bicornuate uterus. The other 3 patients (2 familial cases and 1 sporadic case) shared the same mutation (c.196C>T; p.R66X). However, the clinical features of these patients were highly variable. Additionally, central (meso-axial) polydactyly and deep palmar creases were detected, which have not been previously reported. CFNS has a wide clinical spectrum, but there is no clear genotype-phenotype correlation. However, central (meso-axial) polydactyly and deep palmar creases may be part of the clinical spectrum seen in CFNS. In addition, our findings expand the mutational spectrum in patients with CFNS.

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Section: Discussionmentioning

confidence: 91%

Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel EFNB1 Gene Mutation

Gürsoy¹,

Hazan²,

Öztürk³

et al. 2021

Mol Syndromol

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Corder

Berland

Førsvoll

et al. 2021

American J of Med Genetics Pt A

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Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low‐risk variants. Four Zn‐finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn‐finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2‐related phenotypic variability. The most prevalent phenotypic feature is post‐axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.

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“…Several researchers also reported the incidence of PPD to be as high as 0.08 to 1.4 per 1,000 live births, while the prevalence of PAP is 1-2/1,000 live births with some ethnic group differences (Manske et al, 2017;Ullah et al, 2019a;Ullah et al, 2019b). In humans, until now, 11 genes (GLI3, GLI1, ZRS regulating LMBR1, IQCE, ZNF141, PITX1, MIPOL1, FAM92A, STKLD1, KIAA0825, and DACH1) and three other unknown loci have been mapped on different chromosome 13q21-32, 13q13.3-21.2, and 19p13.1-13.2, which have been linked with isolated polydactyly (Yousaf et al, 2020). However, eight of the 11 genes have been associated with isolated PAP type A including GLI family zinc finger three gene (GLI3; OMIM 174200; 7p14.1), zinc finger protein 141 gene (ZNF141; OMIM 615226; 4p16), GLI family zinc finger 1 (GLI1; OMIM 618123; 12q13.3), IQ Motif Containing E (IQCE; OMIM 617642; 7p22.3), KIAA0825 (OMIM 618498; 5q15), family with sequence similarity 92 member A1 (FAM92A; OMIM 618219; 8q22.1), and Dachshund Homolog 1 (DACH1; OMIM 603803) (Kalsoom et al, 2013;Umair et al, 2017Umair et al, , 2021 (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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

Umair

Ahmad

Ahmad³

et al. 2021

Front. Genet.

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Background: Polydactyly is a prevalent digit abnormality characterized by having extra digits/toes. Mutations in eleven known genes have been associated to cause nonsyndromic polydactyly: GLI3, GLI1, ZRS regulating LMBR1, IQCE, ZNF141, PITX1, MIPOL1, FAM92A, STKLD1, KIAA0825, and DACH1.Method: A single affected family member (IV-4) was subjected to whole-exome sequencing (WES) to identify the causal gene. Bi-directional Sanger sequencing was performed to segregate the identified variant within the family. In silico analysis was performed to investigate the effect of the variant on DNA binding properties.Results: whole-exome sequencing identified a bi-allelic missense variant (c.1010C > T; p. Ser337Leu) in exon nine of GLI1 gene located on chromosome 12q13.3. With the use of Sanger sequencing, the identified variant segregated perfectly with the disease phenotype. Furthermore, in silico analysis of this DNA binding protein revealed that the variant weakened the DNA binding interaction, resulting in indecorous GLI1 function.Conclusion: Herein, we report a novel variant in GLI1 gene, causing autosomal recessive post-axial polydactyly type A (PAPA) type 8. This confirms the critical role of GLI1 in digit development and might help in genotype–phenotype correlation in the future.

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Novel heterozygous sequence variant in the GLI1 underlies postaxial polydactyly

Cited by 7 publications

References 14 publications

Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel <b><i>EFNB1</i></b> Gene Mutation

Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel <b><i>EFNB1</i></b> Gene Mutation

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

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

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