Previously Unexplained Birth Defects Rooted in Genetic Mutations

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A mutation in the WLS gene causes Zaki syndrome, a newly identified disorder characterized by multiorgan birth defects such as microcephaly, foot syndactyly, and heart defects — suggesting a potential target for treatment.

Homozygous mutations in WLS were observed in 10 children who shared similar structural birth defects with no previously identified genetic or environmental cause. Microcephaly and short stature were observed in all 10 children, who also presented some combination of the following:

  • Delayed global milestones
  • Visual impairment
  • Cerebellar hypoplasia and enlarged fourth ventricle in the brain
  • Syndactyly and ectrodactyly

The partial loss-of-function mutations in WLS were determined to be passed by recessive inheritance and resulted in the patients producing significantly less WLS protein compared to healthy peers, reported Joseph Gleeson, MD, of Rady Children’s Institute for Genomic Medicine and the University of California San Diego, and colleagues in the New England Journal of Medicine.

Clinical differences among the Zaki cohort may be attributed to genetic and environmental modifiers, the researchers noted.

WLS is a receptor protein and central regulator of the Wnt proteins that play roles in development and homeostasis of nearly all animals.

“Some of the features of this new condition implicate specific Wnts … Rather than affecting a single Wnt, WLS is required for secretion of all Wnts, so the range of phenotypes probably reflects global or partial depletion across all early Wnt signaling,” the investigators added.

They tested investigational drug CHIR99021, which stimulates Wnt signaling, in a mouse model of Zaki syndrome. They administered the drug twice daily during the development of the embryos, and found that many of the birth defects associated with Zaki syndrome were either partially or fully rescued. Notably, mice who received the drug had larger brains and longer tails than controls, the group reported.

“Our findings suggest that pharmacologic intervention could be considered for some structural birth defects during gestation,” the study authors said. “We did not evaluate postnatal use of CHIR99021, but we do not rule out potential benefit, because we suspect that most future diagnoses of this condition will be made after rather than before birth.”

As of 2017, congenital birth defects were responsible for 21% of infant deaths in the U.S. and were the leading cause of death in infants. “Despite the widespread prevalence of structural birth defects, only a minority of such events can be traced to environmental or genetic causes; in most, causes remain unexplained,” Gleeson and colleagues noted.

For their study, the authors probed worldwide databases of 20,248 families with children with neurodevelopmental disorders.

The smoking gun for mutant WLS came from genetic analysis of a family from the United Arab Emirates in which the parents were first cousins and all five children presented with the same phenotype. Further evidence was gathered from a second family, counting two children from a consanguineous Egyptian family, and three non-consanguineous families with one affected child each.

Families 2 and 3 had identical mutations to each other, while families 4 and 5 presented with independent WLS mutations.

In testing dermal tissue from the child in family 3, the researchers observed that levels of WLS protein were 90% lower than a healthy control.

In order to confirm the effects of the isolated mutations, the researchers developed mouse models with two of the WLS mutations. “We observed globally reduced Wnt reporter activity across the body [of the mice], most notably in facial structures, the heart, the spinal region, the tail bud, the metanephros, and neural tissues — many of the same tissues affected in patients,” they reported.

As for microcephaly related to the WLS mutation, the mutant mice showed cell cycle stalling in developing neural cells, consistent with previous studies on Wnt signaling in the cell cycle. As a result of the defunct cell development, the brains of the embryonic mice were unable to form properly.

“Development of preclinical models for the treatment of amenable structural defects could represent future studies within pediatrics,” according to Gleeson’s team.

Disclosures

This study was funded by grants from the NIH, the Simons Foundation Autism Research Initiative, the Yale Center for Mendelian Genomics, the Broad Institute Center for Mendelian Genomics, the Center for Inherited Disease Research, the Howard Hughes Medical Institute, the Rady Children’s Institute for Genomic Medicine, the National Medical Research Council Open Fund, Singapore’s National Research Foundation, Switzerland’s Branco Weiss Foundation, the European Molecular Biology Organization Young Investigator program, and the Agency for Science, Technology, and Research in Singapore.

Gleeson reported no disclosures.

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