Unexpected phenotype in a frameshift mutation of PTCH1

Abstract

Background Gorlin syndrome, also known as basal cell nevus syndrome (BCNS), is a rare autosomal dominant genetic condition, characterized by the presence of multiple basal cell carcinomas at a young age, odontogenic keratocysts, skeletal anomalies, macrocephaly, and dysmorphisms. BCNS is mainly caused by mutations in PTCH1, an onco‐suppressor gene that maps at 9q22.3 region. A disease related to BCNS is the 9q22.3 microdeletion syndrome. This condition has an overlapping clinical phenotype with the BCNS, but it can present in addition: metopic craniosynostosis, overgrowth, obstructive hydrocephalus, developmental delay, intellectual disability, and seizures. This syndrome is caused by the deletion of a genomic region containing the PTCH1 and the FANCC. Methods and Results We report the case of an 11‐year‐old girl that came to our attention for overgrowth, dysmorphic features of the face, and craniosynostosis, but with a normal intellectual and motor development. At first we performed an array‐comparative genomic hybridization (aCGH) analysis. The analysis showed no copy number changes. Then, we performed the analysis of the PTCH1 by next‐generation sequencing. This analysis showed a heterozygous frameshift mutation. Conclusion This is the first case with a PTCH1 point mutation with a 9q22.3 microdeletion syndrome phenotype. This finding may strengthen the importance of the role of the PTCH1, especially regarding the metopic craniosynostosis.

Microdeletion of 9q22.3: A patient with minimal deletion size associated with a severe phenotype

“…Reduced levels of PTCH1 as in our patient and the truncation of the protein before this point as in the patient discussed above (Beltrami et al, 2020) may explain the extensive phenotype, although other BCNS patients with truncating mutations which would remove this domain but with mild/late onset disease have also been reported (Reinders et al, 2018). Other authors (Wicking et al, 1997) have attributed all the congenital features of BCNS to haploinsufficiency, since the majority of mutations, including some that occur 5 0 to the mutation in the patient of Beltrami and colleagues (Beltrami et al, 2020) would result in premature termination (see also (Reinders et al, 2018) and http://www.lovd.nl/). Therefore, it seems unlikely that the severity is due simply to the nature of the PTCH1 deletion.…”

“…A recent case report presents a patient who was found to be heterozygous for a frame shift mutation (single base insertion) at the beginning of exon 11 of PTCH1 (p.Val502Gly_fs*13) (Beltrami et al, 2020). Although the mutation affected only PTCH1 , the patient had some manifestations of 9q22.3 deletion syndrome.…”

18F-FDG PET/CT findings in nevoid basal cell carcinoma syndrome: a systematic review and a new case report

“…This disease has the estimated prevalence of 1/57000 to 1/256000 and both sexes are equally affected [ 8 ]. The patched-1 (PTCH1) gene, an onco-suppressor gene that maps at 9q22.3 region, is the major causative gene of NBCCS, which involves in the hedgehog signaling pathway [ 9 , 10 ]. The mutation is transmitted in an autosomal dominant inheritance from parents to their children.…”