Submission Details

PGAP3 was first reported in relation to autosomal recessive hyperphosphatasia with intellectual disability syndrome 4 in 2014 (Howard et al., PMID: 24439110). Common phenotypes in individuals with PGAP3 pathogenic variants include severe global developmental delay, speech and language delay, intellectual disability, hypotonia, ataxia, seizures, distinct facial abnormalities (including broad nasal bridge and tip, short nose, long palpebral fissures, hypertelorism, long philtrum, thin and wide upper lip, large ear lobes, and full cheeks), autistic behaviour and sleep disturbances. Additionally, some patients exhibit cleft palate and microcephaly, decreased intrauterine fetal movements, cardiac problems, abnormal corpus callosum, and olfactory bulb agenesis.

Nineteen homozygous and compound heterozygous variants (13 missense, 1 splicing, 2 frameshift, 2 nonsense, and 1 UTR), reported in seven publications have been included in this curation (PMIDs: 24439110, 27120253, 29531774, 30217754, 30345601, 32726939, 32845056). The presumed mechanism of pathogenicity based on published evidence is loss of function whereby variants in the PGAP3 gene lead to a reduction in functional GPI-anchored proteins. This gene-disease relationship is also supported by a zebrafish animal model and protein interaction data (Da'as et al., 2020, PMID: 32726939; Castillon et al., 2013, PMID: 23615438).

In summary, there is definitive evidence supporting the relationship between PGAP3 and autosomal recessive hyperphosphatasia with intellectual disability syndrome 4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date September 5, 2023 (SOP Version 9).

PGAP3 was first reported in relation to autosomal recessive hyperphosphatasia with intellectual disability syndrome 4 in 2014 (Howard et al., PMID: 24439110). Common phenotypes in individuals with PGAP3 pathogenic variants include severe global developmental delay, speech and language delay, intellectual disability, hypotonia, ataxia, seizures, distinct facial abnormalities (including broad nasal bridge and tip, short nose, long palpebral fissures, hypertelorism, long philtrum, thin and wide upper lip, large ear lobes, and full cheeks), autistic behaviour, and sleep disturbances. Additionally, some patients exhibit cleft palate and microcephaly, decreased intrauterine fetal movements, cardiac problems, abnormal corpus callosum, and olfactory bulb agenesis.

Nineteen homozygous and compound heterozygous variants (13 missense, 1 splicing, 2 frameshift, 2 nonsense, and 1 UTR) that have been reported in seven publications (PMIDs: 24439110, 27120253, 29531774, 30217754, 30345601, 32726939, 32845056) are included in this curation. The presumed mechanism of pathogenicity is loss of function, whereby variants in PGAP3 lead to a reduction in functional GPI-anchored proteins. This gene-disease relationship is also supported by a zebrafish model and protein interaction data (Da'as et al., 2020, PMID: 32726939; Castillon et al., 2013, PMID: 23615438).

In summary, there is definitive evidence supporting the relationship between PGAP3 and autosomal recessive hyperphosphatasia with intellectual disability syndrome 4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 5, 2023 (SOP Version 9).