Greig Cephalopolysyndactyly Syndrome: Phenotypic Variability Associated with Variants in Two Different Domains of GLI3

Hammal Khan; Sohail Ahmed; Sadia Nawaz; Wasim Ahmad; Muhammad Arshad Rafiq; Abdullah

doi:10.1055/a-1223-2489

Klin Padiatr 2021; 233(02): 53-58
DOI: 10.1055/a-1223-2489

Original Article

Greig Cephalopolysyndactyly Syndrome: Phenotypic Variability Associated with Variants in Two Different Domains of GLI3

Greig-Zephalopolysyndaktylie-Syndrom: Phänotypische Variabilität geht mit Varianten in zwei verschiedenen Domänen von GLI3 einher

Hammal Khan

¹Department of Biosciences, COMSATS University, Islamabad, Pakistan

,

Abdullah,

Sohail Ahmed

³Institute of Biochemistry, University of Balochistan, Quetta, Pakistan

,

Sadia Nawaz

⁴Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan

,

Wasim Ahmad

²Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

,

Muhammad Arshad Rafiq

¹Department of Biosciences, COMSATS University, Islamabad, Pakistan

› Author Affiliations

Abstract

Background GLI3 is a transcriptional regulator of several genes involved in mammalian skeletal development. Mutations in the pleiotropic gene GLI3 may result in different inherited disorders including Greig cephalopolysyndactyly syndrome (GCPS). GCPS is characterized by mild to severe craniofacial and limb malformations.

Methods and Results Here, we report clinical and molecular study of 3 families with GCPS originated in different regions of Pakistan. Sanger sequencing revealed two novel variants including a frameshift [c. 3790_3791InsC, p.(Gly1236Argfs*11)] and a missense [c.1692A>G, p.(His536Arg)], and one previously reported variant [c.1965_1966delAT, p.(His627Glufs*48)] located in 2 different domains of the GLI3.

Conclusion This study not only expanded spectrum of the mutations in the GLI3 but also highlighted phenotypic variability in the GCPS patients. This will facilitate diagnosis and genetic counseling of families with same and related disorders in the Pakistani population.

Zusammenfassung

Hintergrund GLI3 ist ein Transkriptionsregulator von mehreren Genen mit Einfluss auf die Skelettentwicklung bei Säugetieren. Mutationen im pleiotropen Gen GLI3 können verschiedene Erbkrankheiten zur Folge haben. Eine dieser Krankheiten ist das Greig-Zephalopolysyndaktylie-Syndrom (GCPS), das durch leichte bis schwere Missbildungen des Gesichtsschädels und der Extremitäten charakterisiert ist.

Methodik und ErgebnisseWir berichten über eine klinische und molekulare Studie zu drei Familien mit GCPS, die aus verschiedenen Regionen Pakistans stammten. Die Sanger-Sequenzierung fand zwei neuartige Varianten, ein Frameshift [c. 3790_3791InsC, p.(Gly1236Argfs* 11)] und eine Missense [c.1692A > G, p.(His536Arg)], sowie eine bereits berichtete Variante [c.1965_1966delAT, p.(His-627Glufs*48)], die auf zwei verschiedenen Domänen von GLI3 gelegen sind.

SchlussfolgerungDie vorliegende Studie erweiterte nicht nur das Spektrum der detektierten Mutationen im GLI3-Gen, sondern machte auch die phänotypische Variabilität bei GCPS-Patienten deutlich. Dadurch wird die Diagnostik und humangenetische Beratung von Familien mit diesem Syndrom und verwandten Störungen in der pakistanischen Bevölkerung erleichtert.

Key words

GLI3 - Greig cephalopolysyndactyly syndrome - Novel variants - Phenotypic variability - Sanger sequencing

Schlüsselwörter

GLI3 - Greig-Zephalopolysyndaktylie-Syndrom - neuartige Varianten - phänotypische Variabilität - Sanger-Sequenzierung

Full Text

References

References
1 Abdullah. Yousaf M, Azeem Z. et al. Variants in GLI3 Cause Greig Cephalopolysyndactyly Syndrome. Genet Test Mol Bioma 2019; 23: 744-750
2 Biesecker LG. The Greig cephalopolysyndactyly syndrome. Orphanet J Rare Dis 2008; 3: 10
3 Biesecker LG. What you can learn from one gene: GLI3. J Med Genet 2006; 43: 465-469
4 Dai P, Akimaru H, Tanaka Y. et al. Sonic Hedgehog-induced Activation of the Gli1 Promoter Is Mediated by GLI3. J Biol Chem 1999; 274: 8143-8152
5 Altaba AR. Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 1999; 126: 3205-3216
6 Ito S, Kitazawa R, Haraguchi R. et al. Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas. Diagn Pathol 2018; 13: 1
7 Johnston JJ, Olivos-Glander I, Killoran C. et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet 2005; 76: 609-622
8 Pettersen EF, Goddard TD, Huang CC. et al. UCSF Chimera – a visualization system for exploratory research and analysis. J Comput Chem 2004; 25: 1605-1612
9 Radhakrishna U, Bornholdt D, Scott HS. et al. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 1999; 65: 645-655
10 Richards S, Aziz N, Bale S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-423
11 Sheth R, Bastida MF, Ros M. Hoxd and Gli3 interactions modulate digit number in the amniote limb. Dev Biol 2007; 310: 430-441
12 Temtamy SA, McKusick VA. The genetics of hand malformations. Birth Defects 1978; 14 i