Study Finds Possible Cause and Treatment for Certain Structural Birth Defects

Study Finds Possible Cause and Treatment for Certain Structural Birth Defects
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A new collaborative study finds that genetic variations in a central Wnt regulator—WLS—can cause syndromic structural birth defects and a condition they are calling Zaki syndrome. The researchers also showed that, in preclinical studies, a pharmacologic Wnt agonist can partially restore proper embryonic development, suggesting Zaki is preventable. Results were published in New England Journal of Medicine.

This work was led by scientists of the Rady Children’s Institute for Genomic Medicine, San Diego, and A*STAR, Singapore. They used biobank data from Centogene and other organizations to identify the study cohort.

Peter Bauer, Chief Genomic Officer at Centogene, said, “Up until now, the genetic causes of structural birth defects have remained largely unknown. This groundbreaking study has now not only helped us to understand a driving factor of these defects, but has shed light on the way to a potential cure – and that is game changing. That is what we are striving for every day.”

Structural birth defects, such as cleft palate and microcephaly occur in approximately 3% of live births worldwide, leaving about 4 million babies with such anomalies.

In this study, 20,248 families with children suffering from neurodevelopmental disorders, also featuring parental consanguinity, were identified. Approximately one-third of the affected children presented with structural birth defects. Those patients then underwent exome and genome sequencing to identify genes with biallelic pathogenic or likely-pathogenic mutations.

The analysis revealed that genetic variations affecting a central Wnt regulator – WLS – cause syndromic structural birth defects.

The Wnt signalling pathway regulates cellular development, particularly at the embryonic stage. WLS encodes the Wnt ligand secretion mediator (also known as Wntless or WLS). The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.

The researchers found 10 affected persons from 5 unrelated families. Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling.

The team then generated two mouse models to understand the disease pathophysiology and to test candidate treatments. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.

The administration of a pharmacologic Wnt agonist partially restored embryonic development in the mouse model, suggesting a path forward for an actual drug against Zaki.

“The study results are a perfect reflection of the significance of data and cross-institutional collaboration,” says Aida Bertoli-Avella, Head of Research Data Analysis at Centogene, and one of the study authors. “The findings have helped us gain a deeper understanding of syndromic structural birth defects and put us on the right path with preclinical models – offering a next step towards advancing widespread pharmacological treatments.”

Centogene has developed a global proprietary rare disease platform based on our real-world data repository with over 3.9 billion weighted data points from approximately 600,000 patients representing over 120 different countries. The Company’s platform also includes epidemiologic, phenotypic, and genetic data, as well as a biobank of patients’ blood samples and cell cultures.