Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome

Schuurs-Hoeijmakers, Janneke; Oh, Edwin C.; Vissers, Lisenka E.L.M.; Swinkels, Marielle; Gilissen, Christian; Willemsen, M.A.A.P.; Holvoet, Maureen; Steehouwer, Marloes; Veltman, Joris A.; Vries, Bert B.A. de; Bokhoven, Hans van; Brouwer, Arjan P.M. de; Katsanis, Nicholas; Devriendt, Koenraad; Brunner, Han G.

doi:10.1016/j.ajhg.2012.10.013

Cited by 104 publications

(147 citation statements)

References 16 publications

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“…Together, the recurrence of this particular mutation and the absence of mutations at other positions in the gene, strengthens our previous proposal of a dominant-negative or a gain-of-function effect at the protein level [Schuurs-Hoeijmakers et al, 2012]. The mutation is located in the furin cargo binding domain, directly adjacent to a CK2-binding motif that is essential for PACS1 autoregulation and might affect the auto regulatory property of the protein as well as interaction with cargo, or adaptor binding.…”

Section: Discussionsupporting

confidence: 54%

“…We have previously described two unrelated boys with a strikingly similar facial appearance, moderate intellectual disability, and cryptorchidism who carry an identical de novo mutation in PACS1 (NM_0180026.2, OMIM 615009: Mental Retardation, Autosomal Dominant 17) [Schuurs-Hoeijmakers et al, 2012]. 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.…”

Section: Introductionmentioning

confidence: 69%

“…We expect this to change as clinicians become more familiar with the phenotype. The individuals described in this study were collected via two routes: (i) clinicians contacting the corresponding author of our previous study [Schuurs-Hoeijmakers et al, 2012], and (ii) the parents who found each other via social media (there is an active PACS1-parent Facebook community-PACS1 closed group). This second route was a valuable source of information about feeding and behavioral issues and it nicely demonstrated the drive that parents have to meet and share life experiences and concerns, and consult each other about daily problems.…”

Section: Discussionmentioning

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: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

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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“…To establish the pathogenicity of mutations in such candidate ID genes, it is essential to identify additional individuals with an overlapping phenotype and a mutation in the same gene. [3][4][5] With increasing availability of WES in routine diagnostics 6 as well as technological advances facilitating targeted resequencing of candidate ID genes in larger cohorts of samples, 7 chances of finding such additional individuals are increasing. Furthermore, supporting evidence and insights into underlying mechanisms can be obtained from functional studies in cell or animal models.…”

Section: Introductionmentioning

confidence: 99%

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

et al. 2016

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Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

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“…[3][4][5][6] Similarly, largescale WES studies of individuals affected by ID/DD have recently leveraged this phenomenon as supporting evidence of the involvement of a gene in disease. 7,8 This spatial clustering of de novo mutations (DNMs) is typical for missense mutations in genes without clear, or limited numbers of, truncating mutations subsequently degraded by nonsense-mediated mRNA decay, suggesting that these clustered mutations act through a different mechanism than haploinsufficiency (HI).…”

mentioning

confidence: 99%

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

Lelieveld

Wiel

Venselaar

et al. 2017

The American Journal of Human Genetics

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101

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SummaryHaploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.De novo mutations affecting protein-coding genes are a major cause of intellectual disability (ID) and other developmental disorders (DDs). We downloaded all DNMs occurring in individuals with ID/DD from de novo-db version 1.3 14 identified through WES and whole genome sequencing which were then reannotated with our in-house variant annotation pipeline. The de novo mutations included in the analysis were previously validated by a second independent method or showed a high validation rate for a subset of de novo mutations. In addition, we added 1,183 de novo variants identified in the exomes of an in-house ID cohort that was previously published. 8 To further reduce the risk of including sequencing artifacts and/or genotyping errors, we excluded all de novo variants that were present more than once in the ExAC dataset (Table S1). 15 These efforts resulted in 6,495 protein coding DNMs, including 4,061 missense mutations, in 5,302 individuals with ID/DD (Table S2). We set out to determine for any gene whether the observed de novo missense mutations cluster more than expected compared to random permutations. Hereto, we selected for each the longest representative transcript (i.e., part of the GENCODE basic set) 16 and calculated the geometric mean distance d g over all missense DNMs on

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Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome

Cited by 104 publications

References 16 publications

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

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

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

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