Genomics research unravels the etiology of congenital facial weakness

Congenital facial weakness refers to diminished facial movement observed from birth resulting from impaired function of the facial musculature. Individuals affected by congenital facial weakness experience difficulty smiling, expressing facial emotions, and whistling, and they may exhibit facial drooping and articulation challenges. The cause of this condition had previously been unknown, but this week researchers from the University of Wisconsin–Madison and Boston Children’s Hospital published new research on the genetic cause of hereditary congenital facial paresis type 1 (HCFP1).

Bryn Webb, MD, associate professor, Division of Genetics and Metabolism, was co-first author on “Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis,” published in Nature Genetics on June 29, 2023.

The researchers uncovered a noncoding DNA regulatory region consisting of two enhancers and one silencer that play a pivotal role in controlling the expression of the GATA2 gene during facial nerve development. “We identified specific noncoding disease-causing variants, and I generated a mouse model that confirmed the pathogenesis of these variants,” Webb said. “The mice with a duplication of a human enhancer had no whisker movement — the equivalent to a lack of a smile in humans!”

Alan Tenney, PhD, postdoctoral fellow at Boston Children’s Hospital and co-first author, then performed immunohistochemistry using this mouse model, and this in combination with scRNA-seq confirmed the team’s hypothesis that the variants were pathogenic by altering GATA2 expression leading to an increased number of inner efferent neurons and a decreased number of facial motor neurons.

Noncoding variation, which encompasses alterations in DNA that do not encode for protein sequences, has traditionally been overlooked in the understanding of genetic diseases and termed “junk DNA.” However, this newly published research challenges that notion. Through comprehensive analysis of the human genome’s 3 billion base pairs of DNA via whole genome sequencing, combined with meticulous functional analyses, the research team learned it can successfully identify and understand the function of noncoding DNA changes. This significant breakthrough holds promise for future genetic discoveries across various disorders, particularly those that are suspected to be genetic but whose etiology cannot be explained through whole exome sequencing.

“Although detailed functional analyses of specific noncoding variation may take years, as in our case, it is indeed possible to elucidate their roles,” Webb said. “This represents the next frontier in genetics research and genetic discoveries.”

Webb’s collaborators at Boston Children’s Hospital included co-first authors Alan Tenney, PhD, and Alessandro DiGioia, PhD, as well as senior author  Elizabeth Engle, MD, professor of neurology and ophthalmology.

“To solve questions like this, one needs a team of people with multiple complementary areas of expertise,” Engle said. “We think our work provides an example of how to tease out the genetics and mechanisms of inherited disorders involving noncoding variation.”