A novel GLI3c.750delC truncation mutation in a multiplex Greig cephalopolysyndactyly syndrome family with an unusual phenotypic combination in a patient

Abstract

Greig cephalopolysyndactyly (GCPS) syndrome is an autosomal dominant disorder with high penetrance in majority of cases, characterized by a triad of polysyndactyly, macrocephaly and hypertelorism. GCPS is known to be caused by mutations in the transcription factor GLI3 gene (7p13) which results in functional haploinsufficiency of this gene. The present study reports a large multiplex family having 12 members affected with GCPS in 3 generations and several unaffected members showing autosomal dominant pattern of inheritance with complete penetrance. Interestingly an affected member of the family had unusual features including thumb which is although biphalangeal (confirmed with X-ray) but morphologically looks like finger and a unilateral tiny bony outgrown (externally indistinguishable) on the distal phalanx of the first toe of the left foot. This member also presented with mild ichthyosis. Although it is also possible that one or more of these features are coincidentally present in this member and might not be part of GCPS. Resequencing of the GLI3 gene detected a novel frame-shift mutation c.750delC in heterozygous state transmitting in the family and co-segregating with the disorder suggesting it to be the causal for the GCPS phenotype in the family. In silico analysis suggests that this mutation creates a truncated GLI3 protein resulting in its haploinsufficiency leading to GCPS syndrome. Furthermore, genotype-phenotype correlation is supported by the mutation as it lies in the amino terminal domain of the protein.

Keywords: Cephalopolysyndactyly; GCPS; GLI3; India; Limb defects.

Fig. 1

Pedigree of the family with GCPS. Individuals for whom samples were collected are marked with an asterisk (*).

Fig. 2

Photographs of the patients. (A, B, C) Photographs of an affected member representing typical features of GCPS in the family, displaying craniofacial abnormalities (hypertelorism, low set ear, flat and wide nose, frontal bossing), bilateral syndactyly of hand and bilateral preaxial polysyndactyly of feet. (D, E, F) Photographs of the affected individual (II-11) with unusual features in the GCPS family having mild ichthyosis, sparse hair and low set ears, finger like thumb of upper limb, and bilateral syndactyly of lower limb with no visible polydactyly. (G) X-ray of hand showing biphalangeal finger like thumbs in patient II-11. (H) X-ray of feet showing a tiny unilateral outgrowth (arrow) on the distal phalanx of great toe of left foot in patient II-11.

Fig. 3

Sequence electropherograms of exon 7 of GLI3 gene. (A) DNA sequence of an unaffected member (II-8), (B) Frameshift deletion of the single nucleotide C in an affected member (III-8) of the family.

Fig. 4

(A) A part of normal (1581 amino acid) GLI3 protein and (B) a part of the truncated GLI3 protein sequence of 309 amino acids. Letters in red color indicate abnormal amino acid sequence generated due to frameshift caused by 750delC single nucleotide deletion.