University of Oulu

Rahikkala, E., Myllykoski, M., Hinttala, R. et al. Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). Genet Med 21, 2355–2363 (2019).

Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)

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Author: Rahikkala, Elisa1,2; Myllykoski, Matti3,4; Hinttala, Reetta1,3;
Organizations: 1PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
2Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland
5Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu, Finland
6Kaiser Franz Josef Hospital with G.v. Preyer Children’s Hospital, Department of Pediatrics, Vienna, Austria
7Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
8Neuromuscular Research Department, Medical University of Vienna, Centre for Anatomy and Cell Biology, Vienna, Austria
9Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
10The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
11Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
12Texas Children’s Hospital, Houston, TX, USA
13Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
14Northern Finland Laboratory Centre NordLab and Medical Research Centre, Oulu
15University Hospital and University of Oulu, Oulu, Finland
16Department of Pathology, Oulu University Hospital, Oulu, Finland
17Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
18Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
19Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland
20Baylor Genetics, Houston, TX, 77021, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.7 MB)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2020-02-25


Purpose: A 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.

Methods: International 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.

Results: Five 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.

Conclusions: Biallelic 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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Series: Genetics in medicine
ISSN: 1098-3600
ISSN-E: 1530-0366
ISSN-L: 1098-3600
Volume: 21
Pages: 2355 - 2363
DOI: 10.1038/s41436-019-0503-4
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was supported by the Academy of Finland Grants 266719 and 308009, the S. Jusélius Foundation, the Emil Aaltonen Foundation, and the Jane and Aatos Erkko Foundation to P.K.
Academy of Finland Grant Number: 266719
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
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