Submission Details

PACS1 was first reported in relation to autosomal dominant Schuurs-Hoeijmakers syndrome in 2012 (Schuurs-Hoeijmakers et al., 23159249). At least 2 unique missense variants (NM_018026.4(PACS1):c.607C>T (p.Arg203Trp) & NM_018026.3(PACS1): c.608G>A (p.Arg203Gln)) have been reported in humans. All but one reported cases are due to the Arg203Trp mutation. Miyake et al. 2018 (PMID: 28975623) reported the first and only case of Arg203Gln and described the same distinctive facial dysmorphisms characteristic of the Schuurs-Hoeijmakers syndrome. These features typically include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, large ears, bulbous tip of nose, flat philtrum, wide mouth with downturned corners and thin upper lip with a wavy profile, and diastema of the teeth. Other common phenotypes include intellectual disability, delayed speech development, cryptorchidism in males, seizures, hypotonia, and congenital anomalies affecting the heart, brain, or eye. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 12 points. Variants in this gene have been reported in at least 33 probands in nine publications (PMIDs: 23159249, 25522177, 26842493, 28111752, 30113927, 28975623, 29550517, 30690871, 30588754). Among these, six probands from four publications (PMIDs: 23159249, 25522177, 28975623, 30588754) were selected to be scored based on confirmed de novo status, representation of the variant spectrum, diversity in ethnic groups, and variant detection via trio-based exome sequencing. Summary of Experimental Data: 2 points. This gene-disease association is supported by in vivo functional assays in a non-human model organism. To understand the mechanistic basis of the human dysmorphic phenotype, Schuurs-Hoeijmakers et al 2012 (PMID: 23159249) studied the behavior of the p.Arg203Trp substitution in craniofacial cartilaginous structures in zebrafish embryos and found that the expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion and that this phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. In summary, PACS1 is definitively associated with autosomal dominant, Schuurs-Hoeijmakers syndrome also known as the intellectual disability-craniofacial dysmorphism-cryptorchidism syndrome. 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 June 16, 2020 (SOP Version 7).

PACS1 was first reported in relation to autosomal dominant Schuurs-Hoeijmakers syndrome in 2012 (Schuurs-Hoeijmakers et al., PMID: 23159249). At least 2 unique missense variants (NM_018026.4:c.607C>T, p.Arg203Trp and c.608G>A, p.Arg203Gln) have been reported in humans. All but one reported cases are due to the p.Arg203Trp mutation. Miyake et al. (2018, PMID: 28975623) reported the first and only case of p.Arg203Gln and described the same distinctive facial dysmorphisms characteristic of the Schuurs-Hoeijmakers syndrome. These features typically include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, large ears, bulbous tip of nose, flat philtrum, wide mouth with downturned corners and thin upper lip with a wavy profile, and diastema of the teeth. Other common phenotypes include intellectual disability, delayed speech development, cryptorchidism in males, seizures, hypotonia, and congenital anomalies affecting the heart, brain, or eyes.

Variants in this gene have been reported in at least 33 probands in nine publications (PMIDs: 23159249, 25522177, 26842493, 28111752, 28975623, 29550517, 30113927, 30588754, 30690871). Among these, six probands from four publications (PMIDs: 23159249, 25522177, 28975623, 30588754) were selected to be scored based on confirmed de novo status, representation of the variant spectrum, diversity in ethnic groups, and variant detection via trio-based exome sequencing.

This gene-disease relationship is also supported by in vivo functional assays in a non-human model organism. To understand the mechanistic basis of the human dysmorphic phenotype, Schuurs-Hoeijmakers et al. (2012, PMID: 23159249) studied the effect of the p.Arg203Trp substitution in craniofacial cartilaginous structures in zebrafish embryos and found that the expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion and that this phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells.

In summary, PACS1 is definitively associated with autosomal dominant Schuurs-Hoeijmakers syndrome, also known as intellectual disability-craniofacial dysmorphism-cryptorchidism syndrome. 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 June 26, 2020 (SOP Version 7).