PMC6232149_01
a Pedigree displaying the family history (Progeny LLC Free Online Pedigree Tool Application, accessed 14 April 2018). The proband is indicated by the black arrow. (+), indicates the GLI3 variant was detected in peripheral blood DNA; (-), indicates the GLI3 variant was not detected in peripheral blood DNA. Both maternal and paternal families are Chinese. b Partial sequence chromatograms of GLI3 in the proband and his first-degree relatives. The red arrow indicates the presence of GLI3 NM_000168.5:c.2071C>T p.(Gln691*), and the black arrows indicate the wild-type allele. According to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, the GLI3 nonsense variant is considered pathogenic. c Schematic view of the GLI3 gene structure and the pathogenic variants associated with Pallister-Hall syndrome (PHS) reported to date (St. Jude PeCan ProteinPaint application, accessed 14 April 2018). Black arrow indicates the novel nonsense variant detected in our patient. ZFD, zinc-finger domain (amino acids, aa, 462-645); PC, proteolytic cleavage site (aa 703-740); CBP, cyclic AMP-binding protein-binding domain (aa 827-1132); TA2, transactivation domain (aa 1044-1322); TA1 transactivation domain (aa 1376- 1580). The majority of PHS-causing pathogenic variants are frameshift and nonsense and affect the middle third of the GLI3 gene (aa 666-1161). Pathogenic variants in the remaining sections of GLI3 cause Greig cephalopolysyndactyly syndrome (GCPS), postaxial polydactyly A/B (PAP), and preaxial polydactyly type IV (PPD IV)
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Fig1
Detailed clinical (Table 1) and family (Fig. 1a) histories were taken. He has no family history of PHS or PHS-associated manifestations (Fig. 1a). A novel heterozygous nonsense pathogenic variant in GLI3, NM_000168.5:c.2071C>T p.(Gln691*), was detected (Fig. 1b). In-house Sanger sequencing of peripheral blood DNA from his parents and brother did not detect the GLI3 variant; therefore, his mutation is likely to be de novo (Fig. 1b), although germline mosaicism cannot be excluded and has been previously reported in PHS. There have been more than 40 GLI3 pathogenic variants reported to be associated with either PHS or sub-PHS, where a diagnosis is suspected but does not meet the diagnostic criteria (Fig. 1c).