PACS1 – Schuurs-Hoeijmakers syndrome

Schuurs-Hoeijmakers syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous variants in PACS1, characterized by intellectual disability, global developmental delay and distinctive craniofacial anomalies (Schuurs-Hoeijmakers syndrome). The syndrome was first delineated in two unrelated boys with de novo PACS1 mutations, defining a recognizable syndromic intellectual-disability phenotype (PMID:23159249).

Genetic studies reveal a recurrent de novo heterozygous NM_018026.4:c.607C>T (p.Arg203Trp) variant accounting for the vast majority of cases, identified in ~87 probands across diverse populations (PMID:37747683). Rare missense variants including c.608G>A (p.Arg203Gln) and c.943C>T (p.Arg315Trp) have also been reported. Familial segregation of a novel NM_018026.4:c.755C>T (p.Ser252Phe) variant in a mother–daughter pair supports variant transmissibility and pleiotropy (PMID:37141437). Multi-exon deletions in PACS1 result in attenuated or absent dysmorphic features, indicating that haploinsufficiency is not the primary mechanism (PMID:34373684).

Clinically, patients present with moderate to severe intellectual disability (HP:0001249), delayed speech and language development (HP:0000750), motor stereotypies (HP:0000733), hypertelorism (HP:0000316), epicanthus (HP:0000286), cleft upper lip (HP:0000204), nystagmus (HP:0000639) and esotropia (HP:0000565). Additional findings include coloboma, microcornea and other ocular anomalies, broadening the PACS1 phenotype.

Functional assays demonstrate that mutant PACS1 forms cytoplasmic aggregates with increased protein stability and impaired binding to client proteins. Expression of p.Arg203Trp PACS1 mRNA in zebrafish embryos induces aberrant SOX10-positive cranial neural crest migration and craniofacial defects, consistent with human dysmorphology and indicating a dominant-negative mechanism (PMID:23159249). Variants impeding PACS1–GGA3 adaptor binding further clarify the pathomechanism of syndromic intellectual disability (PMID:37141437).

In human models, iPSC-derived neurons carrying the p.Arg203Trp variant exhibit dysregulated synaptic gene expression and prolonged network burst durations, revealing neurophysiological underpinnings of PACS1 syndrome (PMID:38280846). In PACS1-syndrome mice, antisense oligonucleotide therapy targeting PACS1 or HDAC6 restores dendrite arborization and synaptic transmission, highlighting a potential therapeutic strategy (PMID:36747781).

Despite the rarity of loss-of-function variants causing classical SHMS features, the consistent occurrence of the p.Arg203Trp variant in over eighty unrelated individuals, rigorous functional concordance across species, and segregation data firmly establish a definitive gene-disease relationship.

Key take-home: The recurrent de novo NM_018026.4:c.607C>T (p.Arg203Trp) PACS1 variant causes a dominantly inherited neurodevelopmental syndrome with consistent clinical, genetic, and mechanistic correlates, enabling precise diagnosis and informing targeted therapeutic development.

References

• American Journal of Human Genetics • 2012 • Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. PMID:23159249
• American Journal of Medical Genetics. Part A • 2021 • Prenatal and postnatal diagnosis of Schuurs-Hoeijmakers syndrome: Case series and review of the literature. PMID:33166031
• American Journal of Medical Genetics. Part A • 2023 • Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability? PMID:37141437
• Molecular Biology Reports • 2023 • Genetic characterization of Schuurs-Hoeijmakers syndrome in a moroccan individual with heterozygote PACS1 mutation. PMID:37747683
• Nature Communications • 2024 • iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity. PMID:38280846
• Research Square • 2023 • RNA-targeted therapy corrects neuronal deficits in PACS1 syndrome mice. PMID:36747781

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