PTCH1 – Holoprosencephaly

Holoprosencephaly (HPE) is a congenital midline defect characterized by incomplete separation of the cerebral hemispheres. A single Brazilian female born to consanguineous parents presented with alobar holoprosencephaly, ocular anomalies, and hyperpigmented skin lesions. Genetic testing identified a homozygous PTCH1 missense variant, c.2240T>C (p.Val751Gly), in exon 15, implicating PTCH1 in HPE pathogenesis (PMID:28496998). This variant lies within the sterol‐sensing domain of PTCH1, the receptor for Sonic Hedgehog (SHH), suggesting a loss of function mechanism disrupting SHH‐mediated forebrain patterning.

In a population‐based cohort of sporadic HPE patients from California, no pathogenic PTCH1 variants were detected among >100 cases screened (PMID:10710230), indicating PTCH1 mutations account for a small fraction of HPE. The absence of additional families or segregation data limits genetic evidence to a single proband with no affected relatives.

PTCH1 functions as a negative regulator of SHH signaling; haploinsufficiency or biallelic loss impairs downstream GLI activation, consistent with midline defects observed in murine Ptch1 models. However, no functional assays directly assess the p.Val751Gly variant’s impact on SHH pathway activity in neural development.

Overall, the current evidence supports a Limited association between PTCH1 and holoprosencephaly, pending additional unrelated cases or functional validation. Key Take-home: PTCH1 mutations may underlie rare HPE presentations via disrupted SHH signaling, but further genetic and experimental data are required to confirm clinical utility.

References

• Journal of pediatric genetics • 2017 • Multisystem Involvement in a Patient with a PTCH1 Mutation: Clinical and Imaging Findings. PMID:28496998
• American journal of medical genetics • 2000 • Holoprosencephaly: molecular study of a California population. PMID:10710230

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