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

Genet Med. 2019 Oct;21(10):2355-2363. doi: 10.1038/s41436-019-0503-4.

Elisa Rahikkala ¹ ², Matti Myllykoski ³ ⁴, Reetta Hinttala ⁵ ³, Päivi Vieira ⁵ ⁶, Naemeh Nayebzadeh ⁵ ³, Simone Weiss ⁷, Astrid S Plomp ⁸, Reginald E Bittner ⁹, Mitja I Kurki ¹⁰ ¹¹ ¹², Outi Kuismin ⁵ ¹³ ¹², Andrea M Lewis ¹⁴ ¹⁵, Marja-Leena Väisänen ¹⁶, Hannaleena Kokkonen ¹⁶, Jonne Westermann ⁸, Günther Bernert ⁷, Hannu Tuominen ¹⁷, Aarno Palotie ¹⁰ ¹¹ ¹² ¹⁸ ¹⁹, Lauri Aaltonen ²⁰, Yaping Yang ¹⁵ ²¹, Lorraine Potocki ¹⁴ ¹⁵, Jukka Moilanen ⁵ ¹³, Silvana van Koningsbruggen ⁸, Xia Wang ¹⁵ ²¹, Wolfgang M Schmidt ⁹, Peppi Koivunen ³ ⁴, Johanna Uusimaa ⁵ ³ ⁶

Affiliations

1 PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland. [email protected].
2 Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland. [email protected].
3 Biocenter Oulu, University of Oulu, Oulu, Finland.
4 Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland.
5 PEDEGO Research Unit and Medical Research Centre Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
6 Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu, Finland.
7 Kaiser Franz Josef Hospital with G.v. Preyer Children's Hospital, Department of Pediatrics, Vienna, Austria.
8 Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
9 Neuromuscular Research Department, Medical University of Vienna, Centre for Anatomy and Cell Biology, Vienna, Austria.
10 Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
11 The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
13 Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
14 Texas Children's Hospital, Houston, TX, USA.
15 Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
16 Northern Finland Laboratory Centre NordLab and Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland.
17 Department of Pathology, Oulu University Hospital, Oulu, Finland.
18 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
19 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
20 Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Haartman Institute, Helsinki, Finland.
21 Baylor Genetics, Houston, TX, 77021, USA.

PMID: 30940925 DOI: 10.1038/s41436-019-0503-4

Abstract

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.

Keywords

HIDEA syndrome; P4HTM; exome sequencing; hypoventilation; intellectual disability.

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