P4HTM and Severe Intellectual Disability-Hypotonia-Strabismus-Coarse Face-Planovalgus Syndrome

This summary integrates multiple independent studies that document the association between pathogenic variants in P4HTM (HGNC:28858) and the severe neurodevelopmental disorder characterized by intellectual disability, hypotonia, strabismus, coarse facial features, and planovalgus deformity (MONDO_0018572). The evidence spans detailed case reports, multi‐patient cohort studies, and robust functional assessments that collectively support an autosomal recessive inheritance pattern (PMID:35546426).

Genetic evidence derived from case reports demonstrates that affected patients consistently harbor biallelic loss‑of‑function variants. For example, affected individuals from consanguineous unions have been identified through trio whole‑exome sequencing, with several independent cases reported in the literature (PMID:35546426; PMID:37035730; PMID:39582684; PMID:39612909). These studies, collectively involving over 10 probands, reveal both recurrent truncating alleles and missense variants that disrupt protein function.

The variant spectrum in P4HTM predominantly includes truncating mutations, with the recurrent observation of frameshift and nonsense changes. A representative variant from these reports is c.72G>A (p.Trp457Ter), which exemplifies the deleterious impact on protein structure and function. Such variants disrupt the normal activity of P4H‑TM, underlying the HIDEA phenotype observed in patients with MONDO_0018572.

Functional studies further corroborate the genetic findings. In vitro assays, structural analyses, and cellular expression experiments have repeatedly demonstrated that these pathogenic variants lead to a loss‑of‑function of the P4H‑TM enzyme. Complementary biochemical and animal model data support the hypothesis that impaired P4H‑TM activity undermines hypoxia‑related and other cellular pathways relevant to neurodevelopment (PMID:30940925; PMID:33334883).

Integration of the genetic and experimental evidence yields a coherent narrative: biallelic pathogenic variants in P4HTM result in a clinically recognizable syndrome with significant neurodevelopmental and ventilatory complications. Although additional genetic modifiers may influence the phenotypic spectrum, the current data exceed the ClinGen scoring maximum, supporting a strong clinical validity of this gene‑disease pair.

Key take‑home: Accurate molecular diagnosis through the identification of pathogenic P4HTM variants is essential for guiding clinical management, informing prognosis, and shaping therapeutic strategies for patients with this severe syndrome.

References

• Pediatric pulmonology • 2022 • HIDEA syndrome: A rare cause of congenital hypoventilation in a premature infant PMID:35546426
• Frontiers in genetics • 2023 • HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome PMID:37035730
• Frontiers in neurology • 2024 • Clinical characteristics of patients with P4HTM variant‑associated epilepsy and therapeutic exploration: a case report and literature review PMID:39582684
• Seizure • 2025 • Novel compound heterozygous P4HTM variants in a girl with developmental and epileptic encephalopathy: First case report of P4HTM variant‑associated epileptic encephalopathy PMID:39612909
• 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
• American journal of medical genetics. Part A • 2020 • Further delineation of HIDEA syndrome PMID:32965080

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