Genome sequencing identifies major causes of severe intellectual disability

Gilissen, Christian; Hehir-Kwa, Jayne Y.; Thung, Djie Tjwan; Vorst, Maartje van de; Bon, Bregje W.M. van; Willemsen, Marjolein H.; Kwint, Michael; Janssen, Irene M.; Hoischen, Alexander; Schenck, Annette; Leach, Richard A.; Klein, Robert J.; Tearle, Rick; Bo, Tan; Pfundt, Rolph; Yntema, Helger G.; Vries, Bert B.A. de; Kleefstra, Tjitske; Brunner, Han G.; Vissers, Lisenka E.L.M.; Veltman, Joris A.

doi:10.1038/nature13394

Cited by 1,008 publications

(961 citation statements)

References 29 publications

Supporting

Mentioning

906

Contrasting

Unclassified

Order By: Relevance

“…[1][2][3] The PUF60 (Poly-U Binding Splicing Factor 60 kDa) gene encodes a general splicing factor that facilitates 3′ splice-site recognition at the early stages of spliceosome assembly. 4,5 PUF60 has been partly associated with the rare 8q24.3 microdeletion syndrome phenotype, in particular craniofacial and heart manifestations, in six patients and one fetal case.…”

Section: Introductionmentioning

confidence: 99%

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

et al. 2016

Self Cite

View full text Add to dashboard Cite

International audienceVerheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletio

show abstract

Section: Introductionmentioning

confidence: 99%

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compared to WES, a wider variety of analyses can be performed, in part due to bias in PCR amplification of individual exons in WES, which leads to a heterogeneous profile of read coverage compared to WGS (Gilissen et al. 2014; Meynert et al. 2014).…”

Section: Discussionmentioning

confidence: 99%

A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing

Poulter

Smith

Murrillo

et al. 2015

Molec Gen & Gen Med

View full text Add to dashboard Cite

Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation‐positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase‐PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild‐type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.

show abstract

“…Owing to dropping sequencing costs and optimization of bioinformatics tools, WGS is most likely to take over in the future. 20 In the mean while, targeted resequencing can also provide a higher coverage of selected regions. For large families where linkage data are available, the combination with targeted resequencing can be very powerful.…”

Section: Ngs Findings In Mendelian Epilepsy Disordersmentioning

confidence: 99%

Lessons learned from gene identification studies in Mendelian epilepsy disorders

et al. 2015

View full text Add to dashboard Cite

Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies.

show abstract

Genome sequencing identifies major causes of severe intellectual disability

Cited by 1,008 publications

References 29 publications

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing

Lessons learned from gene identification studies in Mendelian epilepsy disorders

Contact Info

Product

Resources

About