TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities
Wiszniewski W., Hunter JV., Hanchard NA., Willer JR., Shaw C., Tian Q., Illner A., Wang X., Cheung SW., Patel A., Campbell IM., Gelowani V., Hixson P., Ester AR., Azamian MS., Potocki L., Zapata G., Hernandez PP., Ramocki MB., Santos-Cortez RLP., Wang G., York MK., Justice MJ., Chu ZD., Bader PI., Omo-Griffith L., Madduri NS., Scharer G., Crawford HP., Yanatatsaneejit P., Eifert A., Kerr J., Bacino CA., Franklin AIA., Goin-Kochel RP., Simpson G., Immken L., Haque ME., Stosic M., Williams MD., Morgan TM., Pruthi S., Omary R., Boyadjiev SA., Win KK., Thida A., Hurles M., Hibberd ML., Khor CC., Van Vinh Chau N., Gallagher TE., Mutirangura A., Stankiewicz P., Beaudet AL., Maletic-Savatic M., Rosenfeld JA., Shaffer LG., Davis EE., Belmont JW., Dunstan S., Simmons CP., Bonnen PE., Leal SM., Katsanis N., Lupski JR., Lalani SR.
White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ∼70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles. © 2013 The American Society of Human Genetics.