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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. 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. 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. 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.


Elisa Rahikkala, Matti Myllykoski, Reetta Hinttala, Päivi Vieira, Naemeh Nayebzadeh, Simone Weiss, Astrid S Plomp, Reginald E Bittner, Mitja I Kurki, Outi Kuismin, Andrea M Lewis, Marja-Leena Väisänen, Hannaleena Kokkonen, Jonne Westermann, Günther Bernert, Hannu Tuominen, Aarno Palotie, Lauri Aaltonen, Yaping Yang, Lorraine Potocki, Jukka Moilanen, Silvana van Koningsbruggen, Xia Wang, Wolfgang M Schmidt, Peppi Koivunen, Johanna Uusimaa. Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). Genetics in medicine : official journal of the American College of Medical Genetics. 2019 Oct;21(10):2355-2363

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PMID: 30940925

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