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-Cortez & 46 others Gao 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 Boyd, 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 E. Davis, John W. Belmont, Sarah Dunstan, Cameron P. Simmons, Penelope E. Bonnen, Suzanne M. Leal, Nicholas Katsanis, James R. Lupski, Seema R. Lalani

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)197-210
Number of pages14
JournalAmerican Journal of Human Genetics
Volume93
Issue number2
DOIs
StatePublished - Aug 8 2013

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Language Development Disorders
Pediatrics
Gene Frequency
Exons
Brain
Communication Disorders
Premature Aging
Phenotype
Southeastern Asia
Nonsense Codon
Poisons
Haplotypes
Cytoplasm
Proteins
Parents
Cell Membrane
White Matter
Population
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. / Wiszniewski, Wojciech; Hunter, Jill V.; Hanchard, Neil A.; Willer, Jason R.; Shaw, Chad; Tian, Qi; Illner, Anna; Wang, Xueqing; Cheung, Sau W.; Patel, Ankita; Campbell, Ian M.; Gelowani, Violet; Hixson, Patricia; Ester, Audrey R.; Azamian, Mahshid S.; Potocki, Lorraine; Zapata, Gladys; Hernandez, Patricia P.; Ramocki, Melissa B.; Santos-Cortez, Regie L P; Wang, Gao; York, Michele K.; Justice, Monica J.; Chu, Zili D.; Bader, Patricia I.; Omo-Griffith, Lisa; Madduri, Nirupama S.; Scharer, Gunter; Crawford, Heather P.; Yanatatsaneejit, Pattamawadee; Eifert, Anna; Kerr, Jeffery; Bacino, Carlos A.; Franklin, Adiaha I A; Goin-Kochel, Robin P.; Simpson, Gayle; Immken, Ladonna; Haque, Muhammad E.; Stosic, Marija; Williams, Misti D.; Morgan, Thomas M.; Pruthi, Sumit; Omary, Reed; Boyd, Simeon; Win, Kay K.; Thida, Aye; Hurles, Matthew; Hibberd, Martin Lloyd; Khor, Chiea Chuen; Van Vinh Chau, Nguyen; Gallagher, Thomas E.; Mutirangura, Apiwat; Stankiewicz, Pawel; Beaudet, Arthur L.; Maletic-Savatic, Mirjana; Rosenfeld, Jill A.; Shaffer, Lisa G.; Davis, Erica E.; Belmont, John W.; Dunstan, Sarah; Simmons, Cameron P.; Bonnen, Penelope E.; Leal, Suzanne M.; Katsanis, Nicholas; Lupski, James R.; Lalani, Seema R.

In: American Journal of Human Genetics, Vol. 93, No. 2, 08.08.2013, p. 197-210.

Research output: Contribution to journalArticle

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, Boyd, S, 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 2013, 'TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities', American Journal of Human Genetics, vol. 93, no. 2, pp. 197-210. https://doi.org/10.1016/j.ajhg.2013.05.027
Wiszniewski, Wojciech ; Hunter, Jill V. ; Hanchard, Neil A. ; Willer, Jason R. ; Shaw, Chad ; Tian, Qi ; Illner, Anna ; Wang, Xueqing ; Cheung, Sau W. ; Patel, Ankita ; Campbell, Ian M. ; Gelowani, Violet ; Hixson, Patricia ; Ester, Audrey R. ; Azamian, Mahshid S. ; Potocki, Lorraine ; Zapata, Gladys ; Hernandez, Patricia P. ; Ramocki, Melissa B. ; Santos-Cortez, Regie L P ; Wang, Gao ; York, Michele K. ; Justice, Monica J. ; Chu, Zili D. ; Bader, Patricia I. ; Omo-Griffith, Lisa ; Madduri, Nirupama S. ; Scharer, Gunter ; Crawford, Heather P. ; Yanatatsaneejit, Pattamawadee ; Eifert, Anna ; Kerr, Jeffery ; Bacino, Carlos A. ; Franklin, Adiaha I A ; Goin-Kochel, Robin P. ; Simpson, Gayle ; Immken, Ladonna ; Haque, Muhammad E. ; Stosic, Marija ; Williams, Misti D. ; Morgan, Thomas M. ; Pruthi, Sumit ; Omary, Reed ; Boyd, Simeon ; Win, Kay K. ; Thida, Aye ; Hurles, Matthew ; Hibberd, Martin Lloyd ; Khor, Chiea Chuen ; Van Vinh Chau, Nguyen ; Gallagher, Thomas E. ; Mutirangura, Apiwat ; Stankiewicz, Pawel ; Beaudet, Arthur L. ; Maletic-Savatic, Mirjana ; Rosenfeld, Jill A. ; Shaffer, Lisa G. ; Davis, Erica E. ; Belmont, John W. ; Dunstan, Sarah ; Simmons, Cameron P. ; Bonnen, Penelope E. ; Leal, Suzanne M. ; Katsanis, Nicholas ; Lupski, James R. ; Lalani, Seema R. / TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 2. pp. 197-210.
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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.",
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T1 - TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities

AU - Wiszniewski, Wojciech

AU - Hunter, Jill V.

AU - Hanchard, Neil A.

AU - Willer, Jason R.

AU - Shaw, Chad

AU - Tian, Qi

AU - Illner, Anna

AU - Wang, Xueqing

AU - Cheung, Sau W.

AU - Patel, Ankita

AU - Campbell, Ian M.

AU - Gelowani, Violet

AU - Hixson, Patricia

AU - Ester, Audrey R.

AU - Azamian, Mahshid S.

AU - Potocki, Lorraine

AU - Zapata, Gladys

AU - Hernandez, Patricia P.

AU - Ramocki, Melissa B.

AU - Santos-Cortez, Regie L P

AU - Wang, Gao

AU - York, Michele K.

AU - Justice, Monica J.

AU - Chu, Zili D.

AU - Bader, Patricia I.

AU - Omo-Griffith, Lisa

AU - Madduri, Nirupama S.

AU - Scharer, Gunter

AU - Crawford, Heather P.

AU - Yanatatsaneejit, Pattamawadee

AU - Eifert, Anna

AU - Kerr, Jeffery

AU - Bacino, Carlos A.

AU - Franklin, Adiaha I A

AU - Goin-Kochel, Robin P.

AU - Simpson, Gayle

AU - Immken, Ladonna

AU - Haque, Muhammad E.

AU - Stosic, Marija

AU - Williams, Misti D.

AU - Morgan, Thomas M.

AU - Pruthi, Sumit

AU - Omary, Reed

AU - Boyd, Simeon

AU - Win, Kay K.

AU - Thida, Aye

AU - Hurles, Matthew

AU - Hibberd, Martin Lloyd

AU - Khor, Chiea Chuen

AU - Van Vinh Chau, Nguyen

AU - Gallagher, Thomas E.

AU - Mutirangura, Apiwat

AU - Stankiewicz, Pawel

AU - Beaudet, Arthur L.

AU - Maletic-Savatic, Mirjana

AU - Rosenfeld, Jill A.

AU - Shaffer, Lisa G.

AU - Davis, Erica E.

AU - Belmont, John W.

AU - Dunstan, Sarah

AU - Simmons, Cameron P.

AU - Bonnen, Penelope E.

AU - Leal, Suzanne M.

AU - Katsanis, Nicholas

AU - Lupski, James R.

AU - Lalani, Seema R.

PY - 2013/8/8

Y1 - 2013/8/8

N2 - 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.

AB - 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.

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