ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity 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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.