Expanding the phenotype of a recurrent <i>de novo</i> variant in <i><scp>PACS1</scp></i> causing intellectual disability

Gadzicki, Dorothea; Döcker, Dennis; Schubach, Max; Menzel, M.; Schmorl, B.; Stellmer, F.; Biskup, Saskia; Bartholdi, Deborah

doi:10.1111/cge.12544

Cited by 19 publications

(21 citation statements)

References 4 publications

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“…This finding of an identical de novo c.607C>T mutation in two individuals that shared strikingly similar clinical findings, suggested that mutations in PACS1 define a recognizable syndromic form of intellectual disability. A recent report on a third patient with an identical mutation and a similar facial appearance and comparable clinical presentation provided further confirmation of a specific recognizable PACS1-related syndrome [Gadzicki et al, 2014]. In the present publication we report 16 further cases (9 male and 7 female) ages 2-21 years, with the recurrent de novo c.607C>T mutation in PACS1.…”

Section: Introductionsupporting

confidence: 83%

“…All mutations reported here were identified by exome sequencing, and the patients were evaluated in human genetics centers. Previous genetic testing by conventional karyotyping, microarray analysis or targeted gene analysis did not reveal abnormalities, with the exception of a total of five inherited rare CNVs that were detected by microarray analysis in four individuals: two paternally inherited deletions in individual 3 (a 117 kb deletion in 2q13 and a 108 kb deletion in 16p13.2) [Gadzicki et al, 2014], a paternally inherited deletion of 150 kb in 7q11.23 in individual 11, a paternally inherited duplication of 600 kb in 11p11.12, and a 673 kb duplication in 14q32.33 of unknown inheritance in individual 18. All these rare CNVs were considered benign and do not contribute to the phenotype.…”

Section: Geneticsmentioning

confidence: 89%

“…All mutations were identified by exome sequencing in a clinical or research setting from all around the world. We describe the phenotype of these unpublished individuals (including 3 from the Deciphering of Developmental Disorders Study [Deciphering Developmental Disorder Study, 2014]) and the 3 recently reported individuals [SchuursHoeijmakers et al, 2012;Gadzicki et al, 2014] and review their clinical characteristics.…”

Section: Introductionmentioning

confidence: 99%

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Clinical delineation of the PACS1‐related syndrome—Report on 19 patients

Schuurs-Hoeijmakers

Landsverk

Foulds

et al. 2016

American J of Med Genetics Pt A

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We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual “wavy” profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work‐up and management and hope that the present study will facilitate clinical recognition of further cases. © 2016 Wiley Periodicals, Inc.

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Section: Introductionsupporting

confidence: 83%

Section: Geneticsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Clinical delineation of the PACS1‐related syndrome—Report on 19 patients

Schuurs-Hoeijmakers

Landsverk

Foulds

et al. 2016

American J of Med Genetics Pt A

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“…PACS1 p.R203W has been reported previously as a de novo variant from whole-exome sequencing in three unrelated male patients with intellectual disability and similar facial dysmorphisms (Gadzicki et al, 2015; Helbig et al, 2016). Two of these patients had seizures in the neonatal period similar to Patient 5.…”

Section: Resultsmentioning

confidence: 84%

De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

Butler

Silva

Shafir³

et al. 2017

Epilepsy Research

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Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Nav1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

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“…A recurrent de novo missense variant, p.Arg203Trp was identified within the binding domain of PACS1 in nineteen individuals [1-3] who all share an overlapping phenotype including intellectual disability (ID), delayed language development, dysmorphic craniofacial features, and seizures [1-3]. Using whole exome sequencing (WES), we identified eight additional individuals with the same p.Arg203Trp missense variant in PACS1 that we demonstrated were de novo in seven individuals with available parental DNA.…”

mentioning

confidence: 99%