Publications by authors named "Linda Manwaring"

Purpose: Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants.

Methods: In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form.

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Infantile-onset Pompe disease (IOPD) is a rare, severe disorder of lysosomal storage of glycogen that leads to progressive cardiac and skeletal myopathy. IOPD is a fatal disease in childhood unless treated with enzyme replacement therapy (ERT) from an early age. Sickle cell anemia (SCA) is a relatively common hemoglobinopathy caused by a specific variant in the hemoglobin beta-chain.

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Article Synopsis
  • The ITSN1 gene is crucial for brain development, with recent studies showing that de novo variants in this gene are linked to neurodevelopmental disorders, particularly autism and intellectual disability.
  • This study utilized trio exome sequencing on a patient with autism and other cognitive difficulties, along with data from other affected patients globally, to explore the genetic relationships and variants within the ITSN1 gene.
  • The findings revealed ten new patients with specific ITSN1 variants, indicating a strong connection to disorders such as autism and intellectual disability, and suggested that different types of mutations in ITSN1 affect its function and are more common in certain regions of the gene.
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Article Synopsis
  • Large-scale statistical analyses identify disease-gene relationships but fail to accurately represent how specific genetic variations affect observable traits and disease mechanisms.
  • The study focuses on the SATB1 gene, showing that different types of variants lead to similar yet distinct neurodevelopmental disorders, revealing notable genotype-phenotype relationships.
  • Variants causing strong chromatin binding lead to severe disorders, while those causing mild effects highlight the need for detailed studies on specific mutations to better understand the complexities of genetic diseases.
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Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported.

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Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1.

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Purpose: Evaluation of the clinician's role in the optimal interpretation of clinical exome sequencing (ES) results.

Methods: Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results.

Results: The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%).

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Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings.

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Background: Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated.

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Purpose: Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood.

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Background: Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions.

Methods: Eighteen subjects (ages 5.

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A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43-1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum.

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Background: X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants.

Methods: Array CGH analysis was performed using chromosomal microarray with ∼105 000 oligonucleotides covering the entire genome.

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Objective: To describe a novel germline missense mutation in exon 2 of the MEN1 gene identified in a man with multiple endocrine neoplasia type 1 (MEN 1).

Methods: We describe the patient's clinical, laboratory, and genetic data, and we review the relevant literature.

Results: A 41-year-old man with a history of primary hyperparathyroidism and left lower parathyroidectomy presented with nausea, vomiting, and hematemesis.

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Background: Optic pathway gliomas (OPGs) are common pediatric brain tumors that pose significant clinical challenges with regard to predicting which tumors are likely to become symptomatic and require treatment. These tumors can arise sporadically or in the context of the inherited cancer predisposition syndrome neurofibromatosis type 1 (NF1). Few studies have suggested biological or imaging markers that predict the clinical course of this disease.

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