May 2024
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11 Reads
Genetics in medicine: official journal of the American College of Medical Genetics
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May 2024
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11 Reads
Genetics in medicine: official journal of the American College of Medical Genetics
April 2024
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42 Reads
NEJM AI
April 2024
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18 Reads
Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol, important signaling molecules involved in many cellular processes. PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here we describe three unrelated individuals with de novo heterozygous missense variants in PLCG1 (p.Asp1019Gly, p.His380Arg, and p.Asp1165Gly) who exhibit variable phenotypes including hearing loss, ocular pathology and cardiac septal defects. To model these variants in vivo , we generated the analogous variants in the Drosophila ortholog, small wing ( sl ). We created a null allele sl T2A and assessed the expression pattern. sl is broadly expressed, including in wing discs, eye discs, and a subset of neurons and glia. Loss of sl causes wing size reductions, ectopic wing veins and supernumerary photoreceptors. We document that mutant flies exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in sl T2A mutant rescues the loss-of-function phenotypes whereas expressing the variants causes lethality. Ubiquitous overexpression of the variants also reduces viability, suggesting that the variants are toxic. Ectopic expression of an established hyperactive PLCG1 variant (p.Asp1165His) in the wing pouch causes severe wing phenotypes, resembling those observed with overexpression of the p.Asp1019Gly or p.Asp1165Gly variants, further arguing that these two are gain-of-function variants. However, the wing phenotypes associated with p.His380Arg overexpression are mild. Our data suggest that the PLCG1 de novo heterozygous missense variants are pathogenic and contribute to the features observed in the probands.
April 2024
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5 Reads
Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol, important signaling molecules involved in many cellular processes. PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here we describe three unrelated individuals with de novo heterozygous missense variants in PLCG1 (p.Asp1019Gly, p.His380Arg, and p.Asp1165Gly) who exhibit variable phenotypes including hearing loss, ocular pathology and cardiac septal defects. To model these variants in vivo , we generated the analogous variants in the Drosophila ortholog, small wing ( sl ). We created a null allele sl T2A and assessed the expression pattern. sl is broadly expressed, including in wing discs, eye discs, and a subset of neurons and glia. Loss of sl causes wing size reductions, ectopic wing veins and supernumerary photoreceptors. We document that mutant flies exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in sl T2A mutant rescues the loss-of-function phenotypes whereas expressing the variants causes lethality. Ubiquitous overexpression of the variants also reduces viability, suggesting that the variants are toxic. Ectopic expression of an established hyperactive PLCG1 variant (p.Asp1165His) in the wing pouch causes severe wing phenotypes, resembling those observed with overexpression of the p.Asp1019Gly or p.Asp1165Gly variants, further arguing that these two are gain-of-function variants. However, the wing phenotypes associated with p.His380Arg overexpression are mild. Our data suggest that the PLCG1 de novo heterozygous missense variants are pathogenic and contribute to the features observed in the probands.
April 2024
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415 Reads
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2s role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
April 2024
Molecular Genetics and Metabolism
April 2024
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2 Reads
Molecular Genetics and Metabolism
April 2024
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19 Reads
The American Journal of Human Genetics
March 2024
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67 Reads
Human Genetics
Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial–mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.
March 2024
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66 Reads
The American Journal of Human Genetics
... Together, these data indicate that HNRNPC is indispensable in AML cells, yet dispensable for normal cell survival, which agrees with a previous reports showing the dispensability of HNRNPC in mouse embryonic stem cells barring effects on neurodevelopment. 18,19 We next evaluated the functional importance of HNRNPC in AML by comparing in vivo engraftment of AML HNRNPC-kd versus HNRNPC-NT cells. Human AML cells (MV4-11) with HNRNPC depletion failed to engraft in hematopoietic tissues (i.e., bone marrow, spleen, liver) of sub-lethally irradiated mice compared to Table 9), lower HNRNPC expression in AML cells was associated with prolonged survival and was an independent predictor of survival ( Figure 3M). ...
August 2023
The American Journal of Human Genetics
... However, the mRNA expression of claudin-5 and claudin-1 in SNAP-treated HBMECs remains unchanged. Likewise, the protein levels of claudin-5 and VE-Cadherin were not altered [13]. ...
July 2023
JCI Insight
... Genotype-phenotype correlations with the functional impact of 1570 individual amino acid substitutions in OTC using a yeast-based functional complementation assay for human OTCD have been evaluated (Caldovic et al., 2015;Lo et al., 2023). Furthermore, outside of moderate to severe hyperammonemic events, there is significant association (p = 0.029) between median ammonia levels ≥50 micromole/liter (μM) and decrease in performance on Beery visual motor integration (Lichter-Konecki et al., 2023). Some heterozygous females exhibit severe HA as neonates or infants, while others manifest behavioral, hepatic, or neurologic symptoms including HA later in life or well into adulthood (Chongsrisawat et al., 2018;. ...
July 2023
Pediatric Research
... Beyond snRNA 3' processing, recent evidence has elucidated a broader role for the Integrator in contributing to transcriptional homeostasis; these functions include the 3' processing of non-coding Piwi-interacting RNAs as well as cleavage of nascent mRNAs at RNA polymerase II paused sites to facilitate either gene transcription activation or repression [12][13][14]. Phenotypically, human mutations to the Integrator complex have been linked to severe neurodevelopmental syndrome and developmental ciliopathies resulting in oral-facial digital syndromes [9,15,16]. Analysis of the Cancer Genome Atlas has also revealed an increase in non-synonymous mutations to the Integrator subunits in primary tumour samples [13,17]. In model organisms, the knockdown of Integrator causes developmental arrest and results in a shortened lifespan of C. elegans, and depletion of Integrator in mouse results in cortical neuron migration defects leading to neurological disorders [11,18,19]. ...
April 2023
The American Journal of Human Genetics
... correlation, natural history, prognostication, and anticipatory care. A key consideration in the assessment of ultra-rare conditions for potential "precision therapy" development is the degree to which the patient's clinical trajectory can be anticipated 16,17 . Families who are among the first to receive a diagnosis of an ultra-rare genetic disorder have endorsed frustration with the perceived lack of information and support 18,19 . ...
April 2023
Genetics in medicine: official journal of the American College of Medical Genetics
... Recently, we also reported activating, pathogenic variants in SPTSSA, encoding the small subunit A of SPT, as a cause of a complex form of hereditary spastic paraplegia (cHSP) [70]. In this disease, symptoms emerge in early childhood predominantly with upper motor neuron dysfunction leading to lower extremity spasticity without lower motor neuron disease. ...
January 2023
Brain
... Moreover, studies indicate that increasing vasodilatation elevates skin blood flow, increasing skin temperature [87], which facilitates heat dissipation. In humans, TMEM161B has been reported to regulate cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system [88]. This gene might be important under HS conditions, where the sympathetic nervous system coordinates adjustments in cardiac rhythm and skin blood flow as response to thermal challenges [89,90]. ...
January 2023
Proceedings of the National Academy of Sciences
... Because their numbers are very small on a national scale, these people are extremely isolated and vulnerable [2]. They often have a long delay in diagnosis, spending considerable time and resources in seeking advice and testing, commonly referred to as a diagnostic odyssey [8]. ...
January 2023
Orphanet Journal of Rare Diseases
... There can be hyperammonemia (HA) and lactic acidosis due to secondary inhibition of urea cycle enzymes and the pyruvate dehydrogenase complex, respectively, which become additional contributors to brain injury. (6,7,8,9) MSUD is caused by a genetic defect of the enzyme complex branched chain amino acid (BCAA) dehydrogenase, leading to elevated levels of leucine (and other BCCA) which results in malignant cerebral edema. Pathogenesis is complicated by depletion of neurotransmitters, such as dopamine, gamma aminobutyric acid (GABA) and glutamate, and dysregulation of vasopressin. ...
December 2022
Genetics in medicine: official journal of the American College of Medical Genetics
... However, the transcriptome is specific to tissues/organs, and some genes cannot be detected in clinically accessible tissues such as blood, skin fibroblast cells, or simple tissue samples. Therefore, only variants with splicing damage potential in a particular group of genes can be validated using RT-PCR or RNA-seq (Ketkar et al., 2023). Minigenes can be used to investigate splice errors in vitro but may not reflect splicing events in vivo. ...
December 2022
JAMA The Journal of the American Medical Association