Journal
CLINICAL GENETICS
Volume 102, Issue 5, Pages 444-450Publisher
WILEY
DOI: 10.1111/cge.14203
Keywords
genes; HIDEA; intellectual disability; P4HTM; recessive
Categories
Funding
- Academy of Finland [338446, 3HP-HP-FPA ERN-01-2016/739516]
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HIDEA syndrome is a genetic disorder caused by pathogenic variants in the P4HTM gene. It is characterized by muscular and central hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and increased respiratory distress during pneumonia. This study reports six new patients with HIDEA syndrome and expands knowledge of the genetic and phenotypic spectrum of the disease through clinical data analysis and characterization of P4HTM pathogenic variants.
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.
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