ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30411536 Published in 2018, Gianferante et al. studied 18 families with nevoid basal cell carcinoma syndrome (NBCCS) originally identified for a National Cancer Institute (NCI) gene linkage study. The families underwent targeted PTCH1 testing for the NCI study, and here whole-exome sequencing (WES) and array comparative genomic hybridization (aCGH) were used to identify variants in the 7 families for whom targeted PTCH1 testing had not detected variants. Overall, pathogenic variants in PTCH1 were described in 16 of the 18 families. Of these variants, 5 were frameshifts, 3 were nonsense, 2 were in-frame deletions, 1 involved splicing, and 1 was a gross deletion. The authors did not provide coordinates for the gross deletion, so we could not verify that it included PTCH1 exclusively.
21368767 In 2011, Fujii et al. used PCR followed by RT-PCR to identify variants in PTCH1 in 5 unrelated Japanese patients clinically diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Analysis revealed that 2 patients had a parent with NBCCS while the other 3 patients were sporadic cases. Variants in PTCH1 were identified for all the individuals studied; Fujii et. al identified 1 splice site variant, 1 small insertion, 1 small deletion, and 2 nonsense variants. The authors also noted that each variant identified resulted in a truncated patch-1 protein or nonsense-mediated decay.
29575684 In 2018, Reinders et al. created a database for PTCH1. The database contains 331 previously described variants as well as 110 pathogenic or likely pathogenic variants identified using Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) in patients from either the VU University Medical Center (VUMC) or Maastricht University Medical Centre (MUMC). Of these 110 variants, 42 are frameshift, 29 are nonsense, 14 are missense, 16 are splicing errors, and 8 are either large duplications or deletions. Additionally, 80.0% of the individuals screened for these variants were either suspected or diagnosed cases of basal cell nevus syndrome (BCNS), while the remaining 20% of individuals had a family member with either a confirmed or suspected case of BCNS.

Haploinsufficiency phenotype comments:

Loss of function variants within this gene have been associated with nevoid basal cell carcinoma syndrome. Variants in PTCH1 have also been associated with holoprosencephaly; however, it is believed that this phenotype is caused by gain of function variants (OMIM: #610828 and PMID: 11941477).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
18830227 In 2009, Derwinska et al. used cytogenic analysis, array CGH, FISH analysis, sequence analysis with oligonucleotide coordinates, and PCR on a 21-month-old child displaying failure to thrive, microcephaly, and developmental delay. These analyses were also done on the child?s mother who had had 7 previous miscarriages and whom the authors described as ?mildly delayed.? These analyses found that both the proband and his mother had the same variant: a duplication which included the entire PTCH1 gene as well as the noncoding first exon of the gene FANCC. The authors noted that they do not feel that the inclusion of FANCC is responsible for these phenotypes.

Triplosensitivity phenotype comment:

Another, larger duplication involving PTCH1 has been reported (PMID: 21567912) in a mother and two children with developmental delay, microcephaly, and dysmorphic features. PTCH1 has been postulated to be a candidate gene for the phenotype observed in this duplication, but the potential for the other 14 genes duplicated in the region to have an effect on phenotype cannot be ruled out. Additionally, in 2018, Prontera et al. described a duplication of 9q22.32 involving PTCH1 and 7 other genes in a father and daughter with Schilbach-Rott Syndrome (SRS) (PMID: 30936464).