Diagnostic Odyssey in an Adult Patient with Ophthalmologic Abnormalities and Hearing Loss: Contribution of RNA-Seq to the Diagnosis of a PEX1 Deficiency.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Zellweger Syndrome*/diagnosis ; Zellweger Syndrome*/genetics ; Hearing Loss, Sensorineural*/genetics ; Deafness*; Humans ; ATPases Associated with Diverse Cellular Activities/metabolism ; RNA-Seq ; Retrospective Studies ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Biomarkers ; RNA, Messenger ; Fatty Acids

Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids (VLCFA) are the first line biomarkers for the diagnosis. The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms, with Zellweger syndrome being the most severe and Heimler syndrome the less severe disease. Mild clinical conditions frequently present normal or slight biochemical alterations, making the diagnosis of these patients challenging. In the present study we used a combined WES and RNA-seq strategy to diagnose a patient presenting with retinal dystrophy as the main clinical symptom. Results showed the patient was compound heterozygous for mutations in PEX1 . VLCFA were normal, but retrospective analysis of lysosphosphatidylcholines (LPC) containing C22:0-C26:0 species was altered. This simple test could avoid the diagnostic odyssey of patients with mild phenotype, such as the individual described here, who was diagnosed very late in adult life. We provide functional data in cell line models that may explain the mild phenotype of the patient by demonstrating the hypomorphic nature of a deep intronic variant altering PEX1 mRNA processing.

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PI19/01310 Instituto de Salud Carlos III; Centre for Biomedical Network Research on Rare Diseases; 2017:SGR 1428 Agency for Administration of University and Research; URDCAT project, SLT002/16/00174 Generalitat de Catalunya; PerMed project PerMiM (01KU2016B) German Bundesministerium fur Bildung und Forschung (BMBF)

Keywords: PEX1; RNA-seq; hypomorphic mutation; macular oedema; myopathic facies; retinal dystrophy; sensorineural hearing loss; very-long chain LPC

EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities)
0 (Membrane Proteins)
0 (Biomarkers)
0 (RNA, Messenger)
0 (Fatty Acids)
EC 3.6.4.- (PEX1 protein, human)

Peroxisome biogenesis disorders

Date Created: 20221027 Date Completed: 20221028 Latest Revision: 20221030

20240829

PMC9604267

10.3390/ijms232012367

36293220