Publications by authors named "Daniel J Wegner"

Article Synopsis
  • - The study evaluated the efficacy of telehealth in conducting physical examinations (PE) for individuals with undiagnosed and rare disorders, comparing virtual assessments to in-person examinations.
  • - Results showed high agreement in general appearance and craniofacial features between telehealth and in-person evaluations, with varying levels of agreement for neurological examination components.
  • - Participants reported satisfaction with the telehealth experience, indicating that telehealth is a viable alternative for conducting physical examinations in cases of undiagnosed diseases.
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We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing.

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  • * Through analysis of fibroblasts and a fruit fly model, we found that these variants resulted in decreased lipid droplet formation and impaired gene expression linked to SREBP, indicating disrupted pathway function.
  • * Our findings suggest that SREBF2 variants hinder the cleavage of S1P targets, causing disease symptoms by negatively affecting SREBP1 and SREBP2 activity.
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  • Tubulin is a key component of the cytoskeleton and has various isotypes in animals, but it's unclear how these isotypes influence microtubule structures in different cell types.
  • Research on 12 patients with primary ciliary dyskinesia and mouse models uncovered variants in the tubulin isotype that disrupted the formation of centrioles and cilia, impacting microtubule dynamics.
  • The study identified different variants causing distinct effects on tubulin interactions, allowing for the classification of patients into three types of ciliopathic diseases, highlighting the unique roles of specific tubulin isotypes in cellular functions.
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  • 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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  • 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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The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

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Objectives: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) results from biallelic intronic pentanucleotide repeats in We describe an adult male proband with progressive imbalance, cerebellar atrophy, somatosensory neuronopathy, and absence of peripheral vestibular function for whom clinical testing demonstrated a heterozygous expansion consistent with an unaffected carrier.

Methods: We performed whole-genome sequencing (WGS) on peripheral blood DNA samples from the proband and his unaffected mother. We performed DNA long-read sequencing and synthesized complementary DNA from RNA using peripheral blood from the proband.

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Background: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes.

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ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression.

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Article Synopsis
  • * A clinical trial involving 354 infants evaluated the effect of early versus delayed WGS results on clinical management within 60 days, looking at outcomes like changes in treatment and hospitalization duration.
  • * Results showed that infants who received WGS results earlier were twice as likely to have their management changed compared to those receiving results later, indicating the potential benefits of timely genetic testing in acute care settings.
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Pathogenic biallelic variants in HSD17B3 result in 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency, variable disruption of testosterone production, and phenotypic diversity among 46, XY individuals with differences of sexual development (DSDs). We performed quad whole exome sequencing (WES) on two male siblings with microphallus, perineal hypospadias, and bifid scrotum and their unaffected parents. Both male siblings were compound heterozygous for a rare pathogenic HSD17B3 variant (c.

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Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC.

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  • Genomic sequencing is a crucial tool for identifying genetic issues in rare Mendelian diseases, and while techniques are improving, there’s a need to find common practices and areas for better methods in the diagnostic process.* -
  • A study involved gathering information from a genetic testing lab and 11 clinical sites across the U.S. to understand the computational strategies used in workflow for analyzing genomic data.* -
  • Results showed that while there are solid methods for initial data processing, significant variation exists in later steps, especially in how data is prioritized and integrated, indicating that enhancing detection of certain variants could aid in resolving tough undiagnosed cases.*
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HCFC1, a global transcriptional regulator, has been shown to associate with MMACHC expression. Pathogenic variants in HCFC1 cause X-linked combined methylmalonic acidemia and hyperhomocysteinemia, CblX type (MIM# 309541). Recent studies showed that certain variants in HCFC1 are associated with X-linked intellectual disability with mild or absent metabolic abnormalities.

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Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl/H exchangers function as electric shunts for proton pumping and in luminal Cl accumulation.

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Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels.

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Chromodomain helicase DNA-binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole-genome sequencing (WGS).

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Rare or private, biallelic variants in the (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lung disease. Functional characterization of fewer than 10% of over 200 disease-associated variants (majority missense) suggests either disruption of ABCA3 protein trafficking (type I) or of ATPase-mediated phospholipid transport (type II). Therapies remain limited and nonspecific.

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We present a case of 9p- syndrome with a complex chromosomal event originally characterized by the classical karyotype approach as 46,XX,der(9)t(9;13)(p23;q13). We used advanced technologies (Bionano Genomics genome imaging and 10× Genomics sequencing) to characterize the location of the translocation and accompanying deletion on Chromosome 9 and duplication on Chromosome 13 with single-nucleotide breakpoint resolution. The translocation breakpoint was at Chr 9:190938 and Chr 13:50850492, the deletion at Chr 9:1-190938, and the duplication at Chr 13:50850492-114364328.

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ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase-mediated phospholipid transport into the lamellar bodies (type II mutant).

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Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature.

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B4GALT7 encodes beta-1,4-galactosyltransferase which links glycosaminoglycans to proteoglycans in connective tissues. Rare, biallelic variants in B4GALT7 have been associated with spondylodysplastic Ehlers-Danlos and Larsen of Reunion Island syndromes. Thirty patients with B4GALT7-related disorders have been reported to date with phenotypic variability.

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Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A.

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