Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability

Ligt, Joep de; Willemsen, Marjolein H.; Bon, Bregje W.M. van; Kleefstra, Tjitske; Yntema, Helger G.; Kroes, Thessa; Silfhout, Anneke T. Vulto-van; Koolen, David A.; Vries, Petra de; Gilissen, Christian; Rosario, Marisol del; Hoischen, Alexander; Scheffer, Hans; Vries, Bert B.A. de; Brunner, Han G.; Veltman, Joris A.; Vissers, Lisenka E.L.M.

doi:10.1056/nejmoa1206524

Cited by 1,353 publications

(1,145 citation statements)

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“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…Carvill et al performed massively parallel sequencing in 500 individuals with epileptic encephalopathy and identified four patients with de novo SYNGAP1 mutations [Carvill et al, 2013]. Further patients have been described as part of large next generation sequencing studies of individuals with ID [Vissers et al, 2010; de Ligt et al, 2012; Rauch et al, 2012; Redin et al, 2014]. …”

Section: Introductionmentioning

confidence: 99%

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De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

111

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De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

111

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“…This raises the possibility of the same possible biological activity in humans and implies that the MMR system might play a role in the ART process and affect the outcome. ART offspring are associated with various risks such as preterm delivery, low birth weight, congenital abnormality, and genomic imprinting syndromes (Maher et al, 2003;Kurinczuk et al, 2004;de Ligt et al, 2012). However, it is difficult to establish whether these risks are related to the technology itself or the inherited genetic background.…”

Section: Mmr Alterations and Artmentioning

confidence: 99%

Impact of DNA mismatch repair system alterations on human fertility and related treatments

Liu

Wang

et al. 2016

J. Zhejiang Univ. Sci. B

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DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.

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“…These studies have reported a successful molecular diagnosis in up to 25% of cases in large cohorts of unselected, consecutive patients [13]. Phenotype-driven analyses of exome data have also been investigated with the aim of filtering out common variants and those deemed to be non-pathogenic [14].…”

Section: Introductionmentioning

confidence: 99%

Gene2DisCo: Gene to disease using disease commonalities

Frasca

2017

Artificial Intelligence in Medicine

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Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability

Abstract: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).

Cited by 1,353 publications

References 31 publications

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Impact of DNA mismatch repair system alterations on human fertility and related treatments

Gene2DisCo: Gene to disease using disease commonalities

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