P4HTM – HIDEA Syndrome

P4HTM encodes transmembrane prolyl 4-hydroxylase (P4H-TM), an ER-localized enzyme implicated in collagen and HIF regulation. HIDEA syndrome (MONDO:0032780) is characterized by hypotonia, intellectual disability, eye abnormalities, dysautonomia, epilepsy, and hypoventilation. Initial linkage in a consanguineous family suggested a recessive locus, but causative gene identification awaited larger cohorts.

Autosomal recessive inheritance of biallelic P4HTM variants was confirmed in 12 unrelated probands (PMID:30940925). Segregation analysis across multiple families by Sanger sequencing supported co-segregation of variants with disease. Five distinct homozygous or compound heterozygous P4HTM alleles were reported, including frameshift, nonsense, splice, and missense changes.

The variant spectrum comprises two frameshift alleles (e.g., c.949del (p.Val317fs)), two nonsense alleles (e.g., c.649G>T (p.Gly217Ter)), one splice site deletion (c.1074-11del), and one missense variant (c.1073G>A (p.Arg358His)) (PMID:30940925). No recurrent or founder variants have been described to date. Carrier frequencies are unknown; the syndrome appears exceedingly rare.

Functional assays in insect cells demonstrated that three P4H-TM variants yielded insoluble protein products, indicating loss-of-function (PMID:30940925). Subsequently, crystallographic analysis of human P4H-TM revealed a unique EF domain with Ca²⁺-binding motifs and a conserved dioxygenase core, and structural modeling of HIDEA variants predicted disruption of folding and catalytic activity (PMID:33334883).

The phenotypic spectrum includes global developmental delay with intellectual disability (HP:0001249), early hypotonia (HP:0001252), variable eye anomalies (HP:0000478), autonomic dysfunction, epilepsy, and sleep-disordered breathing culminating in hypoventilation (HP:0002791). Recognition of hypoventilation and sleep apnea informs the need for noninvasive ventilatory support.

Together, the genetic and experimental data meet ClinGen criteria for a Strong gene–disease association. Biallelic loss-of-function P4HTM variants are reliably diagnostic for HIDEA syndrome, enabling genetic counseling, targeted management of respiratory complications, and informing future therapeutic development.

References

• Genetics in Medicine • 2019 • Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). PMID:30940925
• The Journal of Biological Chemistry • 2021 • Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains. PMID:33334883

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