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Published on: August 15, 2019
A founder variant expands the phenotype of WNT7B-related PDAC syndrome
Lama AlAbdi1,2, Zuhair Rahbeeni3, Sateesh Maddirevula2
1Department of Zoology, Collage of Science, King Saud University, Riyadh, Saudi Arabia.
Insights
Genetic variants in WNT7B are linked to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome. This study identifies a novel WNT7B founder variant, expanding the known spectrum of PDAC-associated conditions.
Area of Science:
- Genetics and Developmental Biology
- Human Malformation Syndromes
Background:
- Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a complex congenital disorder with established genetic causes in RARB and STRA6.
- A significant proportion of PDAC cases lack molecular diagnosis, indicating the involvement of other genetic factors.
- Previous research suggested biallelic WNT7B variants as a potential novel etiology for PDAC syndrome, characterized by variable expressivity.
Purpose of the Study:
- To investigate the role of WNT7B in PDAC syndrome by reporting on patients with a novel founder variant.
- To further elucidate the genotypic and phenotypic spectrum of WNT7B-related PDAC syndrome.
- To assess the functional impact of the identified WNT7B variant on WNT7B signaling.
Main Methods:
- Clinical and genetic analysis of three patients from two families presenting with features of PDAC syndrome.
- Identification and characterization of a novel founder variant in the WNT7B gene (c.739C>T; Arg247Trp).
- Functional assessment of the variant's effect on WNT7B signaling activity.
Main Results:
- A novel founder variant in WNT7B (c.739C>T; Arg247Trp) was identified in three patients across two families.
- The phenotypic spectrum associated with this variant ranged from typical PDAC features to isolated genitourinary anomalies, demonstrating variable expressivity.
- The identified WNT7B variant significantly impaired WNT7B signaling activity, consistent with previously reported pathogenic variants.
Conclusions:
- This study provides further evidence supporting WNT7B as a causative gene for PDAC syndrome.
- The identified founder variant expands the known spectrum of WNT7B-related PDAC, highlighting its variable expressivity.
- Understanding the genetic basis of PDAC syndrome, including WNT7B variants, is crucial for accurate diagnosis and genetic counseling.
Abstract:
Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c.739C > T; Arg247Trp). The phenotypic expression of this variant ranges from typical PDAC features to isolated genitourinary anomalies. Similar to previously reported PDAC-associated WNT7B variants, this variant was found to significantly impair WNT7B signaling activity further corroborating its proposed pathogenicity. This report adds further evidence to WNT7B-related PDAC and expands its variable expressivity.
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