Publications by authors named "Patricia G Wheeler"

Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND.

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Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders.

Methods: Patients were identified through targeted or exome sequencing.

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Article Synopsis
  • Misregulation of histone lysine methylation is linked to various cancers and developmental disorders, with the gene DOT1L playing a crucial role in this process.
  • Researchers discovered nine individuals with different mutations in DOT1L, all of whom showed developmental delays and major congenital issues.
  • Functional studies in fruit flies and human cells indicated that these mutations are gain-of-function, leading to increased histone methylation and confirming DOT1L's involvement in a genetic disease.
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  • Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder marked by a variety of symptoms including growth delays, upper limb issues, and other systemic problems, primarily caused by mutations in specific genes associated with the cohesin complex.
  • The majority of CdLS cases (over 60%) are linked to mutations in the NIPBL gene, which leads to the most severe form of the syndrome; other cohesin gene mutations typically result in milder symptoms.
  • The study analyzed the genetic factors in 716 individuals with CdLS to better understand the contributions of cohesin complex genes and identify potential new candidate genes, improving knowledge of genetic variations and their effects on CdLS manifestations.
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  • Researchers found 15 new genetic variants in the PSMC3 gene, linked to a specific type of neurodevelopmental delay and intellectual disability in 23 unrelated patients.
  • Mouse and fruit fly experiments showed that these variants hindered normal neuron growth and learning abilities.
  • The variants were shown to disrupt proteasome function, leading to cellular stress and abnormal immune responses, suggesting a connection between proteasome issues and neurodevelopmental disorders.
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NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.

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Article Synopsis
  • - Synonymous variants can disrupt pre-mRNA splicing, leading to disease-causing transcripts, yet are often neglected in genetic testing without further functional data.
  • - The study focuses on a specific synonymous variant (c.327C>T) in the TECTA gene found in seven individuals with hearing loss, which was shown to activate an unintended splicing site.
  • - Results indicate this variant likely causes autosomal recessive hearing loss and appears to be a founder variant among Latinos of African ancestry, highlighting the need for thorough splicing evaluations in identifying genetic diseases.
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Purpose: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in .

Methods: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays.

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  • Pathogenic variants in the MYT1L gene lead to a neurodevelopmental disorder characterized by features like developmental delays, intellectual disabilities, and behavioral disorders.
  • A study analyzed genetic data from 40 previously unreported patients, adding to a total of 62 patients to better understand the clinical characteristics and genotype-phenotype correlations.
  • The research confirmed key phenotypic traits, introduced new clinical features, and emphasized that patients with certain genetic variants do not show distinct clinical differences, aiding in improved diagnosis and management of the disorder.
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  • Subcellular membranes are rich in dolichol, important for protein glycosylation, but its exact role in organelle function and the endosomal-lysosomal pathway is still unclear.
  • Variants in the DHDDS gene, which is essential for dolichol production, are linked to a form of retinitis pigmentosa and various neurodevelopmental disorders, causing symptoms like epilepsy and movement issues in affected patients.
  • Clinical studies showed that patients with DHDDS mutations experienced neurological decline, cognitive issues, and changes in their lysosomal function, suggesting that these variants primarily affect the enzyme's active site and disrupt normal cell processes.
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Purpose: N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20.

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Purpose: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.

Methods: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.

Results: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS.

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Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously.

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De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband.

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Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4-30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss-of-function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant.

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  • * In a study of 20 individuals with harmful mutations in MORC2, symptoms included developmental delay, intellectual disability, and physical growth issues, alongside signs of neuropathy, though neuropathy was not the main problem.
  • * The findings suggest that these genetic variants cause abnormal epigenetic silencing and expand the known disorders linked to MORC2, including specific brain imaging and eye exam abnormalities resembling Leigh syndrome.
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Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants.

Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized.

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Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase.

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Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects.

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Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl-terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones.

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We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait.

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A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.

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Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis.

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