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

TitleTM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.
Publication TypeJournal Article
Year of Publication2013
AuthorsWiszniewski, 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, MLloyd, Khor, CChuen, Chau, NVan Vinh, 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
JournalAm J Hum Genet
Volume93
Issue2
Pagination197-210
Date Published2013 Aug 8
ISSN1537-6605
KeywordsAge of Onset, Aging, Premature, Asian Continental Ancestry Group, Base Sequence, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 2, Exons, Female, Genetic Predisposition to Disease, Humans, Language Development Disorders, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Sequence Deletion, Tetraspanins
Abstract

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.

DOI10.1016/j.ajhg.2013.05.027
Alternate JournalAm. J. Hum. Genet.
PubMed ID23810381
PubMed Central IDPMC3738832
Grant List089276 / / Wellcome Trust / United Kingdom
5K08NS062711 / NS / NINDS NIH HHS / United States
5U54HG006542 / HG / NHGRI NIH HHS / United States
HL-66991 / HL / NHLBI NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
K23NS078056 / NS / NINDS NIH HHS / United States
P30HD024064 / HD / NICHD NIH HHS / United States
P50-MH094268 / MH / NIMH NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01-HL091771 / HL / NHLBI NIH HHS / United States
R01-NS058529-03 / NS / NINDS NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States