ClinGen Dosage Sensitivity Curation Page

PTCHD1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
25131214 Chaudhry et al. 2015 studied 23 individuals from 16 families with PTCHD1 deletions or truncating mutations along with detailed phenotypic descriptions, concluding that PTCHD1 disruptions are highly penetrant genetic risk factors for NDD's. Of the 16 families three families had truncating mutations in exon 3; five families had exon 1 deletions; seven families had whole gene deletions; and one family had a deletion of exon 2 and 3. All mutations were maternally inherited except for two de novo mutations that resulted in a truncating mutation in one individual and a whole gene deletion in another individual. Four of these families had deletions that included the gene DDX53; the authors conclude that this gene is "an unlikely candidate for contribution to the ASD/ID phenotype because its expression has not been seen in adult or fetal brains." Consistent neurological findings in the solely PTCHD1 haploinsufficient cohort are orofacial hypotonia, mild motor incoordination, ASD, GDD, and severe ID. The authors posit that "hemizygous PTCHD1 LOF causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behavior.?
20844286 Noor et. al 2010 discovered mutations within PTCHD1 in 7 families with ASD and 3 families with ID. A 167 Kb microdeletion spanning exon 1 was found in two brothers: one with ASD and the other with a learning disability and ASD features. A 90 Kb deletion encompassing the entire PTCHD1 gene and 5? exons of the ncRNAS was found in three males with ID in one family. The deletion was validated using qPCR revealing that the deletion was maternally inherited in two affected brothers and their affected uncle. Equivalent changes were not found in male control individuals (p=1.2 x10-5). Functional studies were performed in mice and found to statistically inhibit transcription via the Hedgehog signaling pathway. Microdeletions in the gene, 5? region, and 3? region were identified that disrupted the PTCHD1 gene in males leading to either ASD, ID or learning disability; suggesting involvement of this locus in ~1% of ASD and ID individuals. Gene was found to be expressed in human cortex and cerebellum as well as in mice and drosophila brain.
25533962 Fitzgerald et. al 2015 as a part of the Deciphering Developmental Disorders Study used a genotype driven approach to identify 1,133 children (median age 5.5 yrs) with severe undiagnosed developmental disorder and their parents using a combination of exome sequencing and array-based detection of chromosomal rearrangements. A population-based control dataset of un-transmitted diplotypes was generated using the un-transmitted haplotypes from the parents of the affected probands in 1,080 non-consanguineous trios. To define the rarity of each indel, only CNVRs sharing less than 80% if their boundaries with an CNVE of the same type observed at less than 1% population frequency were classified as rare; no LOF variants in PTCHD1 were found in controls. One male proband with no family history of developmental disorders had a De Novo SNV at Chromosome X g.23411706>T, hemizygous genotype, leading to a nonsense mutation (R>*) validated by DNM and LOF phenotype? blue sclerae, deeply set eye, wide mouth, long philtrum, global developmental delay. One male proband with no family history, had an indel on ChrX g.23411077delC, hemizygous genotype (AC>A), leading to a de novo frameshift mutation ? Global Developmental Delay, abnormal facial shape, sleep disturbance, aggressive behavior, constipation, eczema, drooling, gait disturbance.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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.