ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 24 citations in OpenAlex.
- Multivariable genome-wide analysis elucidates the shared genetic architecture, immunosenescence features, and gut-origin therapeutic targets of ulcerative colitis-associated multisystem inflammation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- What goes on when the lights go off? Using machine learning techniques to characterize a child's settling down period.Frontiers in network physiology · 2025Article
- Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice.Pflugers Archiv : European journal of physiology · 2024Article
- Clinical characteristics of patients withFrontiers in neurology · 2024Article
- Article
- Keeping It in the Family: Consanguinity Reveals P4HTM as a Novel Syndromic Obesity Gene.Diabetes · 2023Article
- Biallelic Mutations in P4HTM Cause Syndromic Obesity.Diabetes · 2023Article
- Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.Communications biology · 2023Article
- HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome.Frontiers in genetics · 2023Article
- Exploring links between 2-oxoglutarate-dependent oxygenases and Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Review
- HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein.Clinical genetics · 2022Review
- Article
- Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.The Journal of biological chemistryArticle
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Authors and funding
26 authors at 10 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeA new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive.
methodsInternational collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot.
resultsFive different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function.
conclusionsBiallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.
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