TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities

Wojciech Wiszniewski, Jill V. Hunter, Neil A. Hanchard, Jason R. Willer, Chad Shaw, Qi Tian, Anna Illner, Xueqing Wang, Sau W. Cheung, Ankita Patel, Ian M. Campbell, Violet Gelowani, Patricia Hixson, Audrey R. Ester, Mahshid S. Azamian, Lorraine Potocki, Gladys Zapata, Patricia P. Hernandez, Melissa B. Ramocki, Regie L.P. Santos-CortezGao Wang, Michele K. York, Monica J. Justice, Zili D. Chu, Patricia I. Bader, Lisa Omo-Griffith, Nirupama S. Madduri, Gunter Scharer, Heather P. Crawford, Pattamawadee Yanatatsaneejit, Anna Eifert, Jeffery Kerr, Carlos A. Bacino, Adiaha I.A. Franklin, Robin P. Goin-Kochel, Gayle Simpson, Ladonna Immken, Muhammad E. Haque, Marija Stosic, Misti D. Williams, Thomas M. Morgan, Sumit Pruthi, Reed Omary, Simeon A. Boyadjiev, Kay K. Win, Aye Thida, Matthew Hurles, Martin Lloyd Hibberd, Chiea Chuen Khor, Nguyen Van Vinh Chau, Thomas E. Gallagher, Apiwat Mutirangura, Pawel Stankiewicz, Arthur L. Beaudet, Mirjana Maletic-Savatic, Jill A. Rosenfeld, Lisa G. Shaffer, Erica Ellen Davis, John W. Belmont, Sarah Dunstan, Cameron P. Simmons, Penelope E. Bonnen, Suzanne M. Leal, Elias Nicholas Katsanis, James R. Lupski, Seema R. Lalani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)197-210
Number of pages14
JournalAmerican journal of human genetics
Issue number2
StatePublished - Aug 8 2013

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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