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A chromosomal deletion associated with changes in the brain's white matter and delayed language acquisition in youngsters from Southeast Asia has been identified. Many such children, described as late-talkers, overcome early speech and language difficulties as they grow.
The finding involved cutting edge technology and two physicians with an eye for the unusual. Dr. Seema R. Lalani, a physician-scientist at the Baylor College of Medicine (BCM) and Dr. Jill V. Hunter, professor of radiology at BCM and Texas Children's Hospital, worked together to identify a genetic change responsible for language delay and brain changes in children, predominantly from Southeast Asia.
Lalani, assistant professor of molecular and human genetics at BCM, is a clinical geneticist and also maintains diagnostic studies called chromosomal microarray analysis, a gene chip that helps identify abnormalities in specific genes and chromosomes, as part of her work at BCM's Medical Genetics Laboratory.
Hunter: "I became intrigued when I kept seeing this small (genomic) change in children, from a large sample of more than 15,000, who were referred for chromosomal microarray analysis at BCM. The children were predominantly Burmese refugees, or of Vietnamese ancestry living in the United States. I began with two children with this deletion at Texas Children's Hospital—and soon realized a pattern of early language delay and brain imaging abnormalities in those from Southeast Asia.
Within a period of two to three years, 13 more families with similar problems, having the same genetic change, were diagnosed. Some children were more affected than others with additional cognitive and neurological problems. But, many were identified as late-talkers who had better non-verbal skills when compared to their verbal performances."
Now, in a report that appears online in the American Journal of Human Genetics, Lalani, Hunter and an international group of collaborators identify a genomic deletion on chromosome 2 that is associated with bright white spots which appear on MRIs of the patient's brain white matter.
This chromosomal deletion on chromosome 2 removes a portion of a gene, known as TM4SF20, which encodes a protein spanning the cellular membrane. Researchers do not yet know the function of the protein, but found this genetic change in children of 15 unrelated families mainly from Southeast Asia.
"This deletion could be responsible for early childhood language delay in a large number of children from this part of the world."
Dr. Seema R. Lalani, Clinical Geneticist and Assistant Professor of Molecular and Human Genetics, the Baylor College of Medicine
Dr. Lalani credits Dr. Wojciech Wiszniewski, an assistant professor of molecular and human genetics at BCM with doing much of the work. Wiszniewski has an interest in genomic disorders and is working under the mentorship of Dr. James R. Lupski, vice chair of the department of molecular and human genetics.
According to Dr. Lupski: "Professor Lalani has made a stunning discovery in that she provides evidence that population-specific intragenic CNV (copy number variation – a deletion or duplication of the chromosome) can contribute to genetic susceptibility of even common complex disease such as speech delay in children."
"In a way, this is a good news story," says Dr. Hunter. There is evidence from family studies that some of these children may do quite well in the future, said Lalani.
Lalani elaborates. "This is a genetic change that is present in 2 percent of Vietnamese Kinh population (an ethnic group that makes up 90 percent of the population in that country). In the 15 families we have identified, all children have early language delay. Some are diagnosed with autism spectrum disorder, and if you do a brain MRI study, you find white matter changes in about 70 percent of them.
We have found this change in children who are Vietnamese, Burmese, Thai, Indonesian, Filipino and and Micronesian. It is very likely that children from other Southeast Asian countries within this geographical distribution also carry this genetic change."
Because these are all within a geographic location, Dr. Lalani suspects that there is an ancient founder effect, meaning that at some point in the distant past, the gene deletion occurred spontaneously in one individual, who then passed it on to his or her children and to succeeding generations.
Dr. Lalani: "It is important to follow these children longitudinally to see how these late-talkers develop as they grow. We have also seen this deletion in children whose parents clearly were late-talkers themselves, but overcame the earlier problems to become doctors and professionals.
The variability within the deletion carriers is fascinating and brings into question genetic and environmental modifiers that contribute to the extent of disease in these children."
Language delays mean the children may speak only two or three words by age 2, in comparison with other children who would generally have between 75-100 word vocabulary by age 2.
While there is evidence that children with this deletion may catch up, it is unclear if they continue to have better non-verbal skills than verbal skills. It is also unclear how the specific brain changes correlate with communication disorders in these children.
In fact, when doctors check the parents of these children, they often find similar white matter changes in the parent carrying the deletion. Hunter is not sure how the gene variation relates to the changes in brain white matter and how all of these result in delay in language.
"Young parents in their 30s should not have age-related white matter changes in the brain and these changes should definitely not be present in healthy children," said Lalani.
Others who took part in this work include Neil A. Hanchard, Chad Shaw, Qi Tian, Anna Illner, Xueqing Wang, Sau W. Cheung, Ankita Patel, Ian Campbell, Patricia Hixson, Audrey R. Ester, Mahshid S. Azamian, Lorraine Potocki, Gladys Zapata, Patricia P. Hernandez, Melissa B. Ramocki, Regie L.P. Santos-Cortez, Gao Wang, Michele K. York, Monica Justice, Zili D. Chu, Heather P. Crawford, Carlos A. Bacino, Adiaha I.A. Franklin, Robin Goin-Kochel, Pawel Stankiewicz, Arthur L. Beaudet, Mirjana Maletic-Savatic, John W. Belmont, Suzanne M. Leal, Muhammad E. Haque, Marija Stosic, and Penelope Bonnen ; all of BCM; Jason R. Willer, Erica E. Davis, and Nicholas Katsanis, all of Duke University Medical Center in Duham, North Carolina; Nirupama S. Madduri, Misti D. Williams, Thomas M. Morgan, Sumit Pruthi and Reed Omary of Vanderbilt University in Nashville, Tennesee; Gunter Scharer of Children's Hospital in Aurora, Colorado, Pattamawadee Yanatatsaneejit and Apiwat Mutirangua of Chulalongkorn University in Bangkok, Thailand; Anna Eifert of the Department of Speech and Language at Texas Children's Hospital; Jeffery Kerr, Gayle Simpson and Ladonna Immken of Dell Children's Medical Center in Austin, Texas; Patricia I. Bader and Lisa Omo-Griffith of Northeast Indiana Genetic Counseling Center in Fort Wayne; Simeon A. Boyadjiev of University of California Davis; Kay K. Win Harlem Hospital Center in New York; Aye Thida of Allcare Pediatrics in Missouri City, Texas; Matthew Hurlesof Wellcome Trust Sanger Institutue in Cambridge, United Kingdom; Martin Lloyd Hibberd and Chiea Chuen Khor of Genome Institute of Singapore; Nguyen Van Vinh Chau, Sarah Dunstan and Cameron Simmons of the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, Thomas E. Gallagher of Tripler Army Medical Center in Honolulu, Hawaii; Jill A. Rosenfeld of Signature Genomic Laboratories of PerkinElmer, Inc. in Spokane, Washington and Lisa G. Shaffer of Paw Print Genetics in Spokane, Washington.
Funding for this work came from the Doris Duke Charitable Foundation and Gillson Longenbaugh Foundation, the National Institutes of Health (RO1-HL091771) and National Institute of Neurological Disorders and Stroke (RO1-NS058529-03, Career Development Award K23NS078056 ( Wiszniewski) and 5K08NS062711), the National Human Genome Research Institute (5U54HG006542), the Molecular Medicine Scholars Program at BCM (HL-66991), the McKnight Endowment for Science, Dana Foundation, and the NIH Intellectual and the Developmental Disabilities Research Grant (P30HD024064), the Children's Medical Network endowed chair in pediatric genetics.
Original press release:http://www.eurekalert.org/pub_releases/2013-06/bcom-gda062513.php