Source of Rare Intellectual Disability Syndrome Discovered

October 07, 2020

New findings from scientists at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago have revealed previously unknown information about the genetic basis for Armfield XLID syndrome, a rare intellectual disability linked to genetic defects in the X chromosome.

Published in Nature Communications, these findings point to defects in mRNA splicing as a major cause for Armfield XLID. This, along with other recent studies, shows a rising class of diseases called spliceosomopathies that interfere with neurodevelopment, according to co-senior author of the study Erica Davis, PhD, member of the Advanced Center for Translational and Genetic Medicine at the Manne Research Institute at Lurie Children’s and associate professor of Pediatrics and Cell and Developmental Biology at Northwestern University Feinberg School of Medicine.

“We had hints from early proteomics reports dating back over 10 years ago that FAM50A might be part of the spliceosome,” said Dr. Davis. “This finding was tucked away in a supplementary table of the journal and never validated, so we were thrilled when our data were consistent with preliminary data reported back in 2008.”

Intellectual disability (ID) affects 1 to 3 percent of people, but is 20 to 30 percent more common in males due to a concentration of genes on the X chromosome that are required for neurodevelopment.

Males only have one X chromosome, so genetic mutations in that one chromosome have a higher likelihood of causing disease compared to females who have two X chromosomes and therefore a “backup” copy. Previous studies have discovered at least 140 genes that cause X-linked intellectual disability (XLID), but more than 80 XLID conditions remain without a genetic diagnosis, according to the authors.

First reported in 1999, Armfield XLID syndrome is characterized by impaired growth and causes dysmorphic facial features and seizures. While the causal region of the X chromosome has been known, the specific gene and underlying cellular process impacted by mutations has eluded investigators for over two decades, according to the authors.

In the current study, investigators used GeneMatcher, an online platform that enables the identification of affected individuals with overlapping phenotypes and gene mutations in order to accelerate disease gene discovery. GeneMatcher revealed four unrelated males who all displayed symptoms similar to Armfield XLID, and each one had different rare mutations in FAM50A.

Using zebrafish models, the investigators knocked out FAM50A to study its effects on early development, finding that the animals exhibited similar physical abnormalities to humans with Armfield XLID syndrome. They also studied the specific mechanisms of the FAM50A variants seen in human patients, and discovered that the mutation caused aberrant mRNA splicing and depletion of genetic material that is vital for neurodevelopment.

Biochemical studies further showed that FAM50A interacts directly with the spliceosome and is critical for excising introns — noncoding regions within genes — out of newly transcribed mRNA.

“This finding offers much needed information for the five families with children affected by this rare condition,” Dr. Davis said. “For the original Armfield XLID family, this has been a more than 20-year journey toward a definitive answer.”

These findings, joined with previous studies of other XLIDs, show that defective splicing is an emergent contributor to this class of syndromes. According to the authors, further investigation is warranted in order to better understand the cause of these conditions and to help find treatments.

“It is important to identify the genetic cause for intellectual disability to improve diagnostics and help families know what to expect as their child grows up and whether other organ systems should be monitored,” Dr. Davis said. “We also hope that knowledge about underlying genetics can be used in the future to identify drugs that can improve quality of life for affected individuals and their families.”

This work was performed in collaboration with co-senior investigators at Greenwood Genetic Center in South Carolina and Chungnam National University in South Korea.

This work was supported by U.S. National Human Genome Research Institute grant T32HG008955; National Institute of General Medical Sciences grant R01GM093937; Cancer Research UK grant C309/A25144; Korean Ministry of Trade, Industry and Energy grant 10063396; National Research Foundation of Korea grant 2018M3A9B8021980; National Institute of Mental Health grant R01MH106826; National Institute of Neurological Disorders and Stroke grant R01NS073854; and the South Carolina Department of Disabilities and Special Needs grant 2015-45.

Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through the Stanley Manne Children’s Research Institute. The Manne Research Institute is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. It is the pediatric training ground for Northwestern University Feinberg School of Medicine. Last year, the hospital served more than 220,000 children from 48 states and 49 countries.