A further contribution to the delineation of epileptic phenotype in PACS2-related syndrome

Terrone, Gaetano; Marchese, Francesca; Vari, Maria Stella; Severino, Mariasavina; Madia, Francesca; Amadori, Elisabetta; Giudice, Ennio Del; Romano, Alfonso; Gennaro, Elena Di; Zara, Federico; Striano, Pasquale

doi:10.1016/j.seizure.2020.05.001

Cited by 15 publications

(27 citation statements)

References 5 publications

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“…Finally, we noted a paternally inherited PACS2 frameshift variant in a Type 1 FCD patient. Phosphofurin acidic cluster sorting ( PACS2 ) has been associated with early‐onset epilepsy and various central nervous system abnormalities, but loss‐of‐function variants (as seen in our patient) are not a known mechanism of disease so we assessed it as a variant of unknown significance (VUS) 43 …”

Section: Resultsmentioning

confidence: 99%

Detection of brain somatic variation in epilepsy‐associated developmental lesions

et al. 2022

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Objective Epilepsy‐associated developmental lesions, including malformations of cortical development and low‐grade developmental tumors, represent a major cause of drug‐resistant seizures requiring surgical intervention in children. Brain‐restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. Methods We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high‐depth targeted DNA sequencing. Results We uncovered candidate disease‐causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen‐activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B‐raf proto‐oncogene, serine/threonine kinase [BRAF], and KRAS proto‐oncogene, GTPase [KRAS]) was associated with low‐grade epilepsy‐associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one‐half of epilepsy‐associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease‐causing variants in genes not yet associated with focal cortical dysplasia. Significance These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

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Section: Resultsmentioning

confidence: 99%

Detection of brain somatic variation in epilepsy‐associated developmental lesions

et al. 2022

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“…We compared the clinical characteristics of the WDR37 ‐related disorder, that is, NOCGUS syndrome and the two PACS ‐related disorders, namely Schuurs‐Hoeijmakers syndrome and EIEE 66, in a tabular form (Table 1) (Dentici et al, 2019; Hay et al, 2020; Kanca et al, 2019; Olson et al, 2018; Reis et al, 2019; Schuurs‐Hoeijmakers et al, 2016; Terrone et al, 2020). Overall, some overlap can be observed among the phenotypic spectra of the three disorders: all three disorders were characterized by epilepsy, intellectual disability, cerebellar atrophy, and similar facial features including arching eyebrows, hypertelorism, down slanting palpebral fissures, a broad nasal root, a thin upper lip, and a wide mouth with a thin upper lip and downturned corners (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of coloboma in both conditions can be attributed to H3/K4, which interacts with KMT2D and CHD7 (Butcher et al, 2017; Moccia et al, 2018; Schulz et al, 2014; Tanaka et al, 2012). Among the 17 patients with PACS2 ‐related disorder reported so far, 5 patients had clear documentation of normal ophthalmologic/fundoscopic examinations (Dentici et al, 2019; Olson et al, 2018; Terrone et al, 2020). Coloboma was only documented in the presently reported patient.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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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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“…Finally, we noted a paternally inherited PACS2 frameshift variant in a Type 1 FCD patient. PACS2 has been associated with early-onset epilepsy and various central nervous system abnormalities but loss-of-function variants (as seen in our patient) are not a known mechanism of disease so we assessed it as a variant of unknown significance (VUS) 36 .…”

Section: Resultsmentioning

confidence: 99%

Detection of brain somatic variation in epilepsy-associated developmental lesions

Bedrosian

Miller

Grischow

et al. 2021

Preprint

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Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. We enrolled 50 children undergoing epilepsy surgery into a translational research study. We performed exome and RNA-sequencing of resected brain tissue samples to identify somatic variation. We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). We confirmed somatic findings using high-depth targeted DNA sequencing. In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. Somatic structural variation accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes (EEF2, NAV2, PTPN11) not yet associated with focal cortical dysplasia. These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

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A further contribution to the delineation of epileptic phenotype in PACS2-related syndrome

Cited by 15 publications

References 5 publications

Detection of brain somatic variation in epilepsy‐associated developmental lesions

Detection of brain somatic variation in epilepsy‐associated developmental lesions

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

Detection of brain somatic variation in epilepsy-associated developmental lesions

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