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Northwestern University Feinberg School of Medicine
Center for Autism and Neurodevelopment

PACS1

PACS1 regulates protein sorting in cells. A specific change in this gene (R203W variant) is linked to PACS1 syndrome, which is a rare neurodevelopmental disorder that causes distinct craniofacial features, intellectual disability, developmental delays, speech difficulties, and other health issues.

 Biological Function

PACS1 gene encodes Phosphofurin acidic cluster sorting protein 1, a multifunctional sorting protein involved in endosome to trans-Golgi Network trafficking.

 Mutations

  • Individuals with PACS1 syndrome share a recurrent de novo missense variant (c.607 C>T) that causes an amino acid substitution from Arginine to Tryptophan at position 203 (p.R203W). There is one reported individual with PACS1 syndrome that has a p.R203Q substitution (Arginine to Glutamine). One PACS1 allele remains unaffected.
  • ClinVar reports multiple pathogenic, likely pathogenic, and variants of uncertain significance in PACS1 gene.

 Incidence

  • PACS1 Syndrome Research Foundation reports 200 known cases of PACS1 syndrome.

 Associated Conditions

PACS1 syndrome, also known as Schuurs-Hoejimakers syndrome.

 Symptoms

Individuals with PACS1 syndrome typically present with:

  • Distinct craniofacial features

  • Intellectual disability

  • Global developmental delay

Some, but not all individuals with PACS1 syndrome may also develop additional symptoms, including:

  • Epilepsy

  • Autism Spectrum Disorder (ASD)

  • Hypotonia (low muscle tone)

  • Feeding difficulties

  • Vision (ocular) anomalies

  • Heart (cardiac) anomalies

  • Structural brain abnormalities

 Research at Northwestern

Research from the Guemez Gamboa Lab at Northwestern University explores the molecular mechanisms underlying PACS1 syndrome. Their work uses iPSC-derived neuronal models to investigate how mutations in the PACS1 gene affect brain development, with a focus on transcriptional changes and therapeutic strategies for rare genetic conditions.

Key publications include:

Rylaarsdam L, Rakotomamonjy J, Pope E, Guemez-Gamboa A.
iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.
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Rylaarsdam L, Reddy T, Guemez-Gamboa A.
In search of a cure: PACS1 Research Foundation as a model of rare disease therapy development.
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 Important publications form other laboratories

Research on PACS1 syndrome has expanded in recent years, highlighting its molecular basis, clinical spectrum, and therapeutic possibilities. These studies explore how PACS1 mutations affect neural development, gene regulation, and potential treatment strategies.

Key publications include:

Schuurs-Hoeijmakers JH, Oh EC, Vissers LE, et al.
Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.
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Van Nuland A, Reddy T, Quassem F, et al.
PACS1-Neurodevelopmental disorder: clinical features and trial readiness.
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Moller-Hansen A, Hejla D, Lee HK, et al.
Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?
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Villar-Pazos S, Thomas L, Yang Y, et al.
Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.
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Nair-Gill E, Bonora M, Zhong X, et al.
Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases.
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Sakaguchi Y, Yoshihashi H, Uehara T, et al.
Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.
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Byrd DT, Han ZC, Piggott CA, Jin Y.
PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.
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Liu Y, Ding H, Yan T, et al.
A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum.
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 Genetic Testing

  • PACS1 Syndrome is caused by a de novo missense variant, meaning it is not inherited from either parent. One copy of PACS1 is affected, while the other copy is not.
  • Whole Exome Sequencing is used to detect pathogenic variants in the PACS1 gene.

 Clinical Trials

Currently, there are no active clinical trials listed for PACS1 syndrome on ClinicalTrials.gov.

 Patient advocacy organizations

The PACS1 Foundation is a patient-led organization dedicated to advancing research, raising awareness, and supporting families affected by PACS1 syndrome. The foundation collaborates closely with researchers and clinicians to drive progress toward effective treatments and a potential cure.

 Social Media Resources

Connect with others in the PACS1 community:

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