PHIP – PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

Chung-Jansen syndrome is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous variants in PHIP, encoding the DCAF14 substrate receptor of the CRL4 E3 ubiquitin ligase complex. This condition presents with developmental delay, intellectual disability, behavioral abnormalities, obesity, and characteristic facial dysmorphisms.

Genetic studies have identified 35 unrelated patients with unique PHIP variants, including truncating, missense, splice-site, and multi-exon deletions, implicating haploinsufficiency as the primary mechanism (35 patients [PMID:34773373]). A subsequent cohort of 23 individuals further corroborated these findings, with de novo occurrence in the majority and inherited variants from mildly affected parents in some cases (23 probands [PMID:36726590]).

Segregation analysis has revealed multiple familial cases, notably the c.40G>A (p.Glu14Lys) variant segregating in a mother–child pair and a novel c.3182C>A (p.Ala1061Glu) variant found in siblings and their mother, supporting autosomal dominant transmission (3 affected relatives in total [PMID:36843271]; [PMID:39437749]).

The variant spectrum is diverse: missense substitutions cluster within functional domains, loss-of-function alleles include frameshifts and nonsense changes, and recurrent variants at Ile307 (p.Ile307Pro) highlight mutational hotspots. The c.40G>A (p.Glu14Lys) change exemplifies a missense variant disrupting PHIP’s proline-rich region.

Clinically, almost all individuals exhibit global developmental delay and intellectual disability (22/23 [PMID:36726590]), behavioral disturbances (20/23), and early-onset obesity (13/23), with variable dysmorphic facial features.

Functional assays demonstrate that PHIP variants impair replication fork progression under stress. DNA fiber analyses of p.Asp488Val and p.Glu963Gly show markedly reduced fork stability, and structural modeling of the I307P truncation predicts increased conformational rigidity and premature termination of the protein (DNA fiber assays [PMID:35863899]; protein modeling [PMID:34773373]).

No studies to date have refuted the PHIP–Chung-Jansen syndrome association. Additional longitudinal and genotype–phenotype correlation studies will refine prognostic assessments.

Key Take-home: Heterozygous PHIP variants cause a clinically recognizable autosomal dominant syndrome of developmental delay, intellectual disability, behavioral challenges, and obesity, with strong genetic and functional evidence supporting diagnostic testing in affected individuals.

References

• American journal of medical genetics. Part A • 2022 • PHIP gene variants with protein modeling, interactions, and clinical phenotypes PMID:34773373
• Frontiers in cell and developmental biology • 2022 • PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals PMID:36726590
• American journal of medical genetics. Part A • 2023 • Chung-Jansen syndrome can mimic Cornelia de Lange syndrome: Another player among chromatinopathies? PMID:36843271
• Cold Spring Harbor molecular case studies • 2022 • PHIP variants associated with Chung-Jansen syndrome disrupt replication fork stability and genome integrity PMID:35863899
• Hormone research in paediatrics • 2024 • Novel Insights: A Novel PHIP Variant in a Family with Severe Early-Onset Obesity PMID:39437749

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