Clinical application of whole-exome sequencing across clinical indications

Retterer, Kyle; Juusola, Jane; Cho, Megan T.; Vitazka, Patrik; Millan, Francisca; Gibellini, Federica; Vertino-Bell, Annette; Smaoui, Nizar; Neidich, Julie; Monaghan, Kristin G.; McKnight, Dianalee; Bai, Renkui; Suchy, Sharon F.; Friedman, Bethany; Tahiliani, Jackie; Pineda-Álvarez, Daniel E.; Richard, Gabriele; Brandt, Tracy; Haverfield, Eden; Chung, Wendy K.; Bale, Sherri J.

doi:10.1038/gim.2015.148

Cited by 823 publications

(741 citation statements)

References 37 publications

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“…Variants identified by WES were evaluated and classified according to published guidelines. 29 The homozygous variant identified in subject 3a was confirmed as homozygous in the similarly affected sibling subject 3b by Sanger sequencing. Whole mitochondrial genome sequencing analysis in blood was performed for subjects 2a and 3a; mtDNA sequence was assembled and analyzed relative to the revised Cambridge Reference Sequence (rCRS) and MITOMAP database as previously described.…”

Section: Whole-exome Sequencingmentioning

confidence: 82%

“…28 Clinical WES testing was performed for subjects 2a, 2b, and 3a and their parents as described. 29 DNA libraries were generated using the SureSelect Human All Exon V4 or Clinical Research Exome kit (Agilent Technologies). Data were mapped to the NCBI hg19/ GRCh37 human genome reference sequence and analyzed using GeneDx's XomeAnalyzer.…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

“…Whole mitochondrial genome sequencing analysis in blood was performed for subjects 2a and 3a; mtDNA sequence was assembled and analyzed relative to the revised Cambridge Reference Sequence (rCRS) and MITOMAP database as previously described. 29 Prior to clinical WES, blood DNA from subjects 2a and 2b were also processed for WES in the Mount Sinai Genomics Core Facility using SureSelect V5 libraries (Agilent). Alignment and variant calling using an in-house GATK-based pipeline, plus variant filtering using Ingenuity Variant Analysis (QIAGEN), were performed as described previously.…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

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Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

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Section: Whole-exome Sequencingmentioning

confidence: 82%

Section: Whole-exome Sequencingmentioning

confidence: 99%

Section: Whole-exome Sequencingmentioning

confidence: 99%

See 1 more Smart Citation

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake

Webb

Stroud

et al. 2017

The American Journal of Human Genetics

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“…[22][23][24] These three variants were confirmed by Sanger sequencing. They were unique events observed in our inhouse database of about 350 exomes (including 75 trios from families with simplex ID) for subject 1 (HUGODIMS and CHU de Nantes); in over 40,000 exomes, including 2,300 trios with various developmental disorders, for subject 2 (Boston Children's Hospital and GeneDX); and in 2,500 trios with autism spectrum disorders for subject 3 (Simons Simplex Collection) ( Figure S2 (Figure 1 and Table S4).…”

Section: Congenital Malformationsmentioning

confidence: 77%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

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Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

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“…[1][2][3] Retterer et al 1 reported exome sequencing in more than 3,000 cases and Yang et al 2 in more than 2,000 cases; together these studies report more than 400 autosomal recessive molecular diagnoses, without a single case of a DNM contributing to the genetic etiology. The Deciphering Developmental Disorders project did not identify enrichment for any functional class of DNMs in autosomal recessive developmental disorder-linked genes.…”

mentioning

confidence: 99%