PEDEGO Research Unit, University of Oulu, Oulu, Finland.
Department of Clinical Genetics and Medical Research Center, Oulu University Hospital, Oulu, Finland.
Clin Genet. 2022 Nov;102(5):444-450. doi: 10.1111/cge.14203. Epub 2022 Aug 19.
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.
HIDEA 综合征是由 P4HTM 的双等位致病性变异引起的。其表型特征为肌肉和中枢性张力减退、通气不足（包括阻塞性和中枢性睡眠呼吸暂停）、智力残疾、自主神经功能障碍、癫痫、眼部异常，以及在肺炎期间呼吸窘迫的发生率增加。在此，我们报告了 6 例由 5 种不同的 P4HTM 双等位变异引起的 HIDEA 综合征新病例，包括 3 种新的变异。我们描述了 2 种芬兰富集的致病性 P4HTM 变异，并证明这些变异存在于起始单倍型中。我们回顾了所有先前发表的 HIDEA 患者的临床数据，并对所有与 HIDEA 相关的已报道的 P4HTM 致病性变异进行了计算机分析。P4HTM 中的所有已知致病性变异均导致过早终止密码子、内含子缺失或影响活性部位或 P4H-TM 蛋白整体稳定性的氨基酸变化。在所有情况下，预计正常的 P4H-TM 酶功能将丧失或严重降低。本报告扩展了对该疾病基因型和表型谱的认识。
