PACS1 Syndrome via the PACS1 Gene

PACS1 syndrome, also known as Schuurs-Hoeijmakers syndrome, is an autosomal dominant disorder characterized by intellectual disability, neurodevelopmental delay, speech and language delay, and dysmorphic facies. These four features are consistent among all affected individuals. Dysmorphic features create a recognizable facial gestalt, and typically include thick and arched eyebrows, long eyelashes, ptosis, hypertelorism, down-slanting palpebral fissures, a bulbous nasal tip, flat philtrum, a wide mouth with corners that point downward and thin upper lip vermillion, widely spaced teeth, and simple, prominent and low-set ears. Other features observed in a majority of affected individuals include seizures, behavioral outbursts and aggression, structural brain abnormalities, and oral aversion. Additional shared features that are observed in less than half of cases include autism, failure to thrive, short stature, microcephaly, hypotonia, congenital heart defects (primarily atrial and ventricular septal defects), gastroesophageal reflux, constipation, eye abnormalities including coloboma, single palmar crease, abnormal skull shape, kidney abnormalities, pes planus, hernia, and cryptorchidism. Some affected individuals develop an unsteady gait, or may lose the ability to walk over time (Stern et al. 2017. PubMed ID: 28111752; Schuurs-Hoeijmakers et al. 2012. PubMed ID: 23159249; Schuurs-Hoeijmakers et al. 2016. PubMed ID: 26842493). The fetal phenotype of this disorder has been described in detail for a single case, in whom absent nasal bone, echogenic bowel, increased nuchal fold, bradyarrhythmia, and abnormal cardiac morphology were the primary findings (Gray et al. 2019. PubMed ID: 31330568). Intrauterine growth retardation and oligohydramnios have also been reported (Schuurs-Hoeijmakers et al. 2016. PubMed ID: 26842493).

PACS1 syndrome is the only known human disorder associated with the PACS1 gene, and surprisingly, all affected individuals have the same recurrent de novo alteration. Males and females are affected equally. Despite being caused by only a single pathogenic variant, this syndrome is nevertheless one of the most common single gene causes of intellectual disability and developmental delay. In a recent PreventionGenetics analysis conducted to identify the most common causes of developmental delay, PACS1 scored within the top 20 causes (Top 99 Genetic Causes of Developmental Delay Panel). Over 30 cases have been described in the literature, and many more exist in the databases of diagnostic labs, including several unpublished cases identified at PreventionGenetics.

While there is currently no treatment for PACS1 syndrome, patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms (such as seizures), or for future family planning decisions. All known cases of PACS1 syndrome are de novo, and no cases with clear germline mosaicism have been documented; therefore, recurrence risk is expected to be very low. Prenatal testing or pre-implantation genetic diagnosis may still be considered for pregnancies of parents with an affected child due to the theoretical possibility of germline mosaicism. Two support organizations exist specific to patients and families affected by PACS1 syndrome, namely the PACS1 foundation (www.pacs1foundation.org) and PACS1 Smiles (www.pacs1smiles.org)(Lusk et al. 1993. PubMed ID: 32672908).

PACS1 syndrome is an autosomal dominant neurodevelopmental disorder caused by de novo pathogenic variants in a single amino acid residue of the PACS1 gene. This residue - p.Arg203 is changed to tryptophan in a large majority of cases (c.607C>T p.Arg203Trp). An alternate missense variant affecting the same amino acid residue (c.608G>A p.Arg203Gln) has also been reported to have occurred de novo in a single affected individual (Miyake et al. 2018. PubMed ID: 28975623). The clinical phenotype of that patient was very similar to patients with the p.Arg203Trp change. Surprisingly, no other variants have been reported as causative in this gene. However, gnomAD restraint metrics for this gene indicate a high gene-level of intolerance for loss of function changes (including a particularly noteworthy dearth of early termination variants in the gnomAD database), suggesting that other changes in this gene may have a more severe early lethal phenotype that is not yet delineated (gnomAD). There are no cases of inherited PACS1 syndrome documented, and no cases of suspected germline mosaicism documented. The disorder appears to be fully penetrant, and expressivity is variable, as observed with many neurodevelopmental disorders (Stern et al. 2017. PubMed ID: 28111752; Schuurs-Hoeijmakers et al. 2012. PubMed ID: 23159249; Schuurs-Hoeijmakers et al. 2016. PubMed ID: 26842493).

The PACS1 gene product, Phosphofurin Acidic Cluster Sorting Protein 1, is located at chromosomal band 11q13.1-q13.2. PACS1's single transcript is comprised of 24 exons, which code for a 963 amino acid protein. This protein acts in the trans-golgi network, where it plays a role in helping to sort and deliver other proteins to their proper locations by shuttling them into endosomes. The single missense alteration causing PACS1 syndrome impairs the ability of this protein to act in its shuttling service, and therefore certain protein products accumulate in the cell or are delivered to the wrong locations (Burgert et al. 2013. PubMed ID: 24001769). PACS1 is widely expressed throughout all tissues. A zebrafish model of PACS1 syndrome recapitulates the human phenotype in its alterations of tissues that form craniofacial structures. While no mouse model of PACS1-syndrome exists to our knowledge, homozygous PACS1 knockout mice (resulting from a frameshift variant) are viable and fertile (Schuurs-Hoeijmakers et al. 2012; The Jackson Laboratory). PACS1 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

A recent PreventionGenetics analysis of the most frequent single-gene causes of developmental delay identified the PACS1 gene within the top 20 causes (Top 99 Genetic Causes of Developmental Delay Panel). Additionally, PACS1 patients have a recognizable facial gestalt. Based on these factors, we expect the clinical sensitivity for this test to be higher than for many other single gene tests for syndromic intellectual disability (<1%). Even so, the clinical and genetic heterogeneity of intellectual developmental disorders is extraordinarily diverse. Based on the wide potential differential diagnosis of most patients with syndromic intellectual disability, we recommend a large panel or exome test as the quickest route to diagnosis. Analytical sensitivity of this test is expected to be near 100%, as this test gets reliable full coverage of the single pathogenic variant causative for PACS1 syndrome, and this pathogenic variation has been reported in several patients tested at PreventionGenetics.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the PACS1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).