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.

Zahra Alsahlawi, Elisa Rahikkala, Peppi Koivunen, Aida M Bertoli-Avella, Johanna Uusimaa, Peter Bauer, Kornelia Tripolszki, Christopher J Carroll, Mehran B Toosi, Javier Martini, Antonio Romito, Minna Kraatari-Tiri, Marie-Christine Nougues, Boris Keren, Christel Depienne, Cyril Mignot, Hanna Kallankari, Jonna Komulainen-Ebrahim, Ehsan G Karimiani, Yalda Jamshidi, Matti Myllykoski, Leila Soikkonen

Journal: Clinical genetics 2022;102(5):444-450

PMID: 35908151

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Abstract

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.

Address: PEDEGO Research Unit, University of Oulu, Oulu, Finland.; Department of Clinical Genetics and Medical Research Center, Oulu University Hospital, Oulu, Finland.; Department of Biomedicine, University of Bergen, Bergen, Norway.; Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.; Department of Genetics, Next Generation Polyclinic, Mashhad, Iran.; Department of Children and Adolescents and Medical Research Center, Oulu University Hospital, Oulu, Finland.; APHP.Sorbonne Université, Département de Génétique, Hôpital Armand Trousseau and Groupe Hospitalier Pitié-Salpêtrière, Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.; Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP.Sorbonne Université, Paris, France.; Département de Neuropédiatrie, APHP.Sorbonne Université, Hôpital Trousseau, Trousseau, France.; Department of Pediatrics, Salmaniya Medical Complex, Kingdom of Bahrain, Bahrain.; Department of Medical Reporting and Genomics, Centogene GmbH, Rostock, Germany.; Department of Pediatrics, School of medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Biocenter Oulu, University of Oulu, Oulu, Finland.; Faculty of Biochemistry and Molecular Medicine, Oulu Centre for Cell-Matrix Research, University of Oulu, Oulu, Finland.

DOI: 10.1111/cge.14203

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MeSH Terms: Amino Acids, Catalytic Domain, Codon, Nonsense, Humans, Intellectual Disability, Muscle Hypotonia, Phenotype, Prolyl Hydroxylases, Syndrome