Association of the missense variant p.<scp>Arg203Trp</scp> in <i><scp>PACS1</scp></i> as a cause of intellectual disability and seizures

Stern, David T.; Cho, M T; Chikarmane, Rashmi; Willaert, Rebecca; Retterer, Kyle; Kendall, Fran; Deardorff, Matthew A.; Hopkins, Sarah; Bedoukian, Emma; Slavotinek, Anne; Vergano, S Schrier; Spangler, Brooke B.; McDonald, Marie; McConkie‐Rosell, Allyn; Burton, Barbara K.; Kim, K H; Oundjian, Nelly Jouayed; Kronn, David; Chandy, Nandini; Baskin, Berivan; Sacoto, María J. Guillen; Wentzensen, Ingrid M.; McLaughlin, Heather; McKnight, Dianalee; Chung, Wendy K.

doi:10.1111/cge.12956

Cited by 26 publications

(31 citation statements)

References 5 publications

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“…Ataxia due to cerebellar hypoplasia, dyspraxia, and stereotypic movements had been reported with the PACS1 mutation (Schuurs-Hoeijmakers et al, 2016;Stern et al, 2017). In Patient 1, trihexyphenidyl hydrochloride altered her movement characteristics.…”

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confidence: 89%

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Schuurs‐Hoeijmakers syndrome in two patients from Japan

Hoshino

Enokizono

Imagawa

et al. 2018

American J of Med Genetics Pt A

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Schuurs‐Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date, 28 patients with a recurrent de novo PACS1 mutation (c.607C > T) have been reported, primarily in Western populations. Here, we describe two Japanese patients with Schuurs‐Hoeijmakers syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each patient presented novel clinical phenotypes. One patient presented with involuntary movements and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1 mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms along with the neurodevelopmental processes. The second patient was diagnosed with lipomyelomeningocele during an examination for severe constipation at the age of 2 years and 8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients with Schuurs‐Hoeijmakers syndrome was not fully recognized, additional studies are needed to clarify the clinical spectrum.

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confidence: 89%

“…Information Table). To our knowledge, 28 patients with a recurrent de novo PACS1 mutation (c.607C > T) have been reported mainly in Western populations (Pefkianaki et al, 2018;Schuurs-Hoeijmakers et al, 2016;Stern et al, 2017); however, the recurrent mutation has never been reported in Asian countries. Brain MRI at 4 months showed no abnormality.…”

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confidence: 93%

Schuurs‐Hoeijmakers syndrome in two patients from Japan

Hoshino

Enokizono

Imagawa

et al. 2018

American J of Med Genetics Pt A

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“…It is now known that the average case is a product of many susceptibility-increasing variations. Only a handful of ASD-related diseases have monogenic causes, such as Rett syndrome, fragile X syndrome, tuberous sclerosis, and Schuurs–Hoeijmakers syndrome (Artuso et al, 2011; Stern et al, 2017; Woodbury-Smith and Scherer, 2018). Dozens of large-scale genetic studies have since been conducted on ASD patients and their families, leading to hundreds of risk genes being identified.…”

Section: Genetics Of Asdmentioning

confidence: 99%

Genetic Causes and Modifiers of Autism Spectrum Disorder

Rylaarsdam

Guemez‐Gamboa

2019

Front. Cell. Neurosci.

367

229

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Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 10–20% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.

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“…PACS1 and PACS2 are two human paralogous genes that each cause a distinctive human disorder. A specific class of mutations in PACS1 , that is, c.607C > T p.(Arg203Trp) and c.608G > A p.(Arg203Gln), results in Schuurs‐Hoeijmakers syndrome (OMIM #615009), characterized by intellectual disability and facial dysmorphism (Dutta, 2019; Hoshino et al, 2019; Pefkianaki et al, 2018; Schuurs‐Hoeijmakers et al, 2012; Schuurs‐Hoeijmakers et al, 2016; Stern et al, 2017). Meanwhile, a specific class of mutations in PACS2 , that is, c.625G > A p.(Glu209Lys) and c.631G > A p.(Glu211Lys), causes early infantile epileptic encephalopathy 66 (EIEE 66) (OMIM #618067) (Olson et al, 2018; Terrone et al, 2020).…”

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confidence: 99%

Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37‐PACS1‐PACS2 axis

Sakaguchi

Yoshihashi

Uehara

et al. 2020

American J of Med Genetics Pt A

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We report a male adult with early infantile‐onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2‐related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large‐scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37‐related disorder and a PACS1‐related disorder (Schuurs‐Hoeijmakers syndrome), but not in a PACS2‐related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37‐PACS1‐PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.

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Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures

Cited by 26 publications

References 5 publications

Schuurs‐Hoeijmakers syndrome in two patients from Japan

Schuurs‐Hoeijmakers syndrome in two patients from Japan

Genetic Causes and Modifiers of Autism Spectrum Disorder

Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37‐PACS1‐PACS2 axis

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