Impact of integrated translational research on clinical exome sequencing

Klee, Eric W.; Cousin, Margot A.; Vairo, Filippo Pinto e; Morales‐Rosado, Joel A.; Macke, Erica L.; Jenkinson, W. Garrett; Ferrer, Alejandro; Schultz‐Rogers, Laura; Olson, Rory J.; Oliver, Gavin R.; Sigafoos, Ashley N.; Schwab, Tanya L.; Zimmermann, Michael T.; Urrutia, Raúl; Kaiwar, Charu; Gupta, Aditi; Blackburn, Patrick R.; Boczek, Nicole J.; Prochnow, Carri A.; Lowy, Rebecca J.; Mulvihill, Lindsay A.; McAllister, Tammy M.; Aoudia, Stacy L.; Kruisselbrink, Teresa M.; Gunderson, Lauren; Kemppainen, Jennifer L.; Fisher, Laura J.; Tarnowski, Jessica M.; Hager, Megan M.; Kroc, Sarah A.; Bertsch, Nicole L.; Agre, Katherine; Jackson, Jessica L.; Macklin-Mantia, Sarah; Murphree, Marine I.; Rust, Laura; Bolster, Jolene M. Summer; Beck, Scott A.; Atwal, Paldeep S.; Ellingson, Marissa S.; Barnett, Sarah S.; Rasmussen, Kristen; Lahner, Carrie A.; Niu, Zhiyv; Hasadsri, Linda; Ferber, Matthew J.; Marcou, Cherisse A.; Clark, Karl J.; Pichurin, Pavel N.; Deyle, David R.; Morava‐Kozicz, Eva; Gavrilova, Ralitza H.; Dhamija, Radhika; Wierenga, Klaas J.; Lanpher, Brendan C.; Babovic‐Vuksanovic, Dusica; Farrugia, Gianrico; Schimmenti, Lisa A.; Stewart, A. Keith; Lazaridis, Konstantinos N.

doi:10.1038/s41436-020-01005-9

Cited by 31 publications

(32 citation statements)

References 46 publications

(47 reference statements)

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“…A 2001 study demonstrated brain development defects in Drosophila models lacking AGO protein 1, including a reduction in the total number of several types of neurons and glial cells 16 . Furthermore, GDD (n = 10), ID (n = 8), autism spectrum disorder (n = 6), epilepsy (n = 5), hypotonia (n = 4), and dysmorphisms (n = 3) were observed among reported individuals (Table 2), which indicates that variants of AGO1 may cause broad‐spectrum neurodevelopmental disorders 4–14 . Our case did not have an autistic phenotype, which is different from the six cases of autism spectrum disorders previously reported in the literature 5,7,10,13 .…”

Section: Discussionmentioning

confidence: 61%

“…In 2019, a de novo missense variant of AGO1 was reported in a 15‐year‐old girl with hypotonia, frequent seizures, and intellectual disability (ID) 4 . To date, only 14 individuals (from different families) have been reported to exhibit intragenic pathogenic variants of AGO1 , and detailed clinical information is available for only three of them 4–14 . In this study, we identify one in‐frame deletion variant, describe four individuals with pathogenic AGO1 variants, and summarize the phenotypic and genotypic spectrum of AGO1‐ related disorders.…”

Section: Introductionmentioning

confidence: 99%

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De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype

Niu

Qian

et al. 2022

Clinical Genetics

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AGO1, as one of the rare genes in neurodevelopmental disorders, is involved in the microRNA‐induced silencing complex. Here, we describe the clinical and genetic features of 18 individuals with de novo AGO1 variants: four new and 14 previously reported. Three variants are identified: two in‐frame deletion variants and one missense variant. The spectrum of AGO1‐related disorders included global development delay (GDD), intellectual disability (ID) with or without epilepsy, autism spectrum disorder, hypotonia and dysmorphisms. Focal seizures are the most common type of seizure, occasionally with atypical absence. Mild deafness may be a new phenotype of AGO1‐releated disease. Gly199Ser may be a hot‐spot variant of AGO1 with the same phenotype: GDD/ID, intractable epilepsy, remarkably with Rolandic discharges, and even reaching electrical status epilepticus during sleep.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

De novo variants in AGO1 recapitulate a heterogeneous neurodevelopmental disorder phenotype

Niu

Qian

et al. 2022

Clinical Genetics

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“…The patient was diagnosed with Dubowitz syndrome in Dyment et al, 2021 [45]. Monies et al, 2015;Lee et al, 2016;Zheng et al, 2016;Bick et al, 2017;Hiejima et al, 2017;Bourgeois et al, 2018;Vardi et al, 2018;Rudilla et al, 2019;Fung et al, 2020;Taher et al, 2020;Dyment et al, 2021;Klee et al, 2021), the incidence of this disease is not significantly different between genders (M:F 17:20) (Table 1). Patients have their onset mostly in the neonatal period, ranging from birth to 0.8 years of age (mean, 29.5 days; median, 17 days).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

et al. 2021

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Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported.Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased.Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.

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“…In the last decade, the technological advancements in sequencing technologies, with the advent of so‐called ‘next‐generation’ approaches, coupled with the access to exponentially increasing computational power and progress in bioinformatics, have led to major progresses and broadened the comprehension of the causes of genetic disorders 1 . These conditions can now be systematically screened in clinical practice at specialized referral centres, allowing to diagnose a large fraction of cases previously classified as ‘cryptogenic’ and to implement the first individualized management approaches 2 …”

Section: Figurementioning

confidence: 99%