TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Goodman, Lindsey D.; Cope, Heidi; Nil, Zelha; Ravenscroft, Thomas A.; Charng, Wu‐Lin; Lu, Shenzhao; Tien, An-Chi; Pfundt, Rolph; Koolen, David A.; Haaxma, Charlotte A.; Veenstra‐Knol, Hermine E.; Wassink-Ruiter, Jolien S. Klein; Wevers, Marijke R.; Jones, Melissa K.; Walsh, Laurence E.; Klee, Victoria H.; Theunis, Miel; Legius, Eric; Steel, Dora; Barwick, Katy; Kurian, Manju A.; Mohammad, Shekeeb S; Dale, Russell C.; Terhal, Paulien A; Binsbergen, Ellen van; Kirmse, Brian; Robinette, Bethany; Cogné, Benjamin; Isidor, Bertrand; Grebe, Theresa A.; Kulch, Peggy; Hainline, Bryan E.; Sapp, Katherine; Morava, Éva; Klee, Eric W.; Macke, Erica L.; Trapane, Pamela; Spencer, Christopher; Si, Yue; Begtrup, Amber; Moulton, Matthew J.; Dutta, Debdeep; Kanca, Oguz; Wangler, Michael F.; Yamamoto, Shinya; Bellen, Hugo J.; Tan, Queenie K.‐G.

doi:10.1016/j.ajhg.2021.06.019

Cited by 29 publications

(12 citation statements)

References 115 publications

(189 reference statements)

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“…Concerning his complex neurocognitive picture, not fully explainable by his WBS diagnosis, trio-WES was performed and a de novo heterozygous likely pathogenic variant was identified in TNPO2 , p.Arg105ter (NM_001136196.2:c.313C>T), consistent with a concurrent novel neurodevelopmental disorder (OMIM #619556) [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…The seventh case was an already diagnosed maternal UPD that concurrently unmasked a pathogenic maternal variant in an included gene. The last case was affected by two de novo diseases: a recurrent microdeletion and an additional dominant TNPO2 -neurodevelopmental disorder; interestingly, only 15 other patients carrying de novo pathogenic variants in TNPO2 have been reported to date [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

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Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients

Rosina

Pezzani

Pezzoli

et al. 2022

Genes

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In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have been estimated to occur in approximately 2–7.5% of diagnosed cases, with higher frequency in consanguineous families. Here, we report the clinical and molecular characterisation of eight illustrative patients for whom trio-WES allowed for identifing more than one genetic condition. Double homozygosity represented the causal mechanism in only half of them, whereas the other half showed peculiar multilocus combinations. The paper takes into consideration difficulties and learned lessons from our experience and therefore supports the powerful role of wide analyses for ascertaining multiple genetic diseases in complex patients, especially when a clinical suspicion could account for the majority of clinical signs. It finally makes clear how a patient’s “deep phenotyping” might not be sufficient to suggest the presence of multiple genetic diagnoses but remains essential to validate an unexpected multilocus result from genetic tests.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients

Rosina

Pezzani

Pezzoli

et al. 2022

Genes

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“…We complemented our rescue-based assays by overexpressing Ref-Tg and SSC-Tg in a wild-type background using ubiquitous ( tub-GAL4 ), eye-specific ( GMR-GAL4 ), and wing-specific ( nub-GAL4 ) drivers ( Figure 4A ). This approach has routinely been employed to discern functional differences between reference and disease-associated variant proteins in vivo , regardless of whether the phenotypic readout has similarities to the patient’s conditions ( Ansar et al, 2019 ; Chung et al, 2020 ; Goodman et al, 2021 ; Harel et al, 2016 ; Huang et al, 2020 ; Kanca et al, 2019 ; Liu et al, 2018 ; Marcogliese et al, 2018 ; Post et al, 2020 ; Ravenscroft et al, 2021 ; Splinter et al, 2018 ). Critically, UAS-Ref-Tg and UAS-SSC-Tg are inserted into the same genomic landing site in the fly genome, and the construct only differs by the point mutation, allowing for direct functional comparison.…”

Section: Resultsmentioning

confidence: 99%

Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases

et al. 2022

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“…4g). Loss-of-function mutations in CDK5 protein were previously associated with lissencephaly [62], and de novo mutations in TNPO2 protein were found within individuals with neurodevelopmental abnormalities [63]. CDCA4 may therefore represent an important master regulator of disease associated genes in progenitors during neural development.…”

Section: Resultsmentioning

confidence: 99%

Inferring cell-type-specific causal gene regulatory networks during human neurogenesis

Aygün

Liang

Crouse

et al. 2022

Preprint

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BackgroundGenetic variation influences both chromatin accessibility, assessed in chromatin accessibility quantitative trait loci (caQTL) studies, and gene expression, assessed in expression QTL (eQTL) studies. Genetic variants can impact either nearby genes (local eQTLs) or distal genes (trans eQTLs). Colocalization between caQTL and eQTL, or local- and distant-eQTLs suggests that they share causal variants. However, pairwise colocalization between these molecular QTLs does not guarantee a causal relationship. Mediation analysis can be applied to assess the evidence supporting causality versus independence between molecular QTLs. Given that the function of QTLs can be cell-type-specific, we performed mediation analyses to find epigenetic and distal regulatory causal pathways for genes within two major cell types of the developing human cortex, progenitors and neurons.ResultsWe found that expression of 168 and 38 genes were mediated by chromatin accessibility in progenitors and neurons, respectively. We also found that the expression of 781 and 200 downstream genes were mediated by upstream genes in progenitors and neurons. Moreover, we discovered that a genetic locus associated with inter-individual differences in brain structure showed evidence for mediation of SLC26A7 through chromatin accessibility, identifying molecular mechanisms of a common variant association to a brain trait.ConclusionsIn this study, we identified cell-type-specific causal gene regulatory networks whereby the impacts of variants on gene expression were mediated by chromatin accessibility or distal gene expression. Identification of these causal paths will enable identifying and prioritizing actionable regulatory targets perturbing these key processes during neurodevelopment.

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TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Cited by 29 publications

References 115 publications

Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients

Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients

Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases

Inferring cell-type-specific causal gene regulatory networks during human neurogenesis

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