PLCH1 and Holoprosencephaly

This summary evaluates the association of PLCH1 with holoprosencephaly based on multi‐patient case reports and functional studies. The evidence is derived from two unrelated families in which homozygous deleterious variants in PLCH1 co‐segregated with a holoprosencephaly spectrum phenotype, including key clinical features such as cyclopia and lobar holoprosencephaly (PMID:33820834).

The clinical validity of this association qualifies as Strong. In total, four probands from two independent families were identified with consistent findings of severe developmental brain malformations. The segregation pattern, where each family showed affected siblings with homozygous variants, and the concordance of experimental data support this categorization (PMID:33820834).

Genetic evidence indicates an autosomal recessive inheritance mode. Reported variants include a frameshift mutation, exemplified by c.3211del (p.Cys1071fs), which was observed in one of the families. Additional affected siblings in each pedigree further strengthen the segregation evidence (PMID:33820834).

The variant spectrum consists of at least two distinct homozygous deleterious mutations, with one variant (c.3211del (p.Cys1071fs)) selected as a representative alteration. This variant meets the criteria for pathogenicity with a clear coding change and appropriate frameshift annotation using three-letter amino acid codes (PMID:33820834).

Functional studies have provided moderate evidence for the impact of these variants. Immunocytochemistry demonstrated that PLCH1 normally displays a cytoplasmic localization in embryonic tissues, while the pathogenic variant shows aberrant nuclear accumulation. This mislocalization, consistent with perturbations in neurodevelopment, aligns with the clinical presentation observed in affected individuals (PMID:33820834).

In conclusion, the integration of genetic and experimental evidence establishes a strong association between PLCH1 and holoprosencephaly. Despite the limited number of families, the consistent genetic findings and supportive functional data underscore the clinical utility of PLCH1 screening in patients presenting with holoprosencephaly spectrum disorders. Key take‑home message: PLCH1 genetic analysis should be considered in the diagnostic evaluation of holoprosencephaly, as it may offer valuable insights for prognosis and therapeutic planning.

References

• Journal of medical genetics • 2022 • Mutations in phospholipase C eta-1 are associated with holoprosencephaly PMID:33820834

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