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; Illner, Anna; Wang, Xueqing; Cheung, Sau Wai; Patel, Ankita; Campbell, Ian; Gelowani, Violet; Hixson, Patricia; Ester, Audrey R.; Azamian, Mahshid S.; Potocki, Lorraine; Zapata, Gladys; Hernandez, Patricia; Ramocki, Melissa B.; Santos‐Cortez, Regie Lyn P.; Wang, Gao; York, Michele K.; Justice, Monica J.; Chu, Zili; Bader, Patricia I.; Omo-Griffith, Lisa; Madduri, Nirupama S.; Scharer, Gunter; Crawford, Heather P.; Yanatatsaneejit, Pattamawadee; Eifert, Anna; Kerr, Jeffery; Bacino, Carlos A.; Franklin, A. I. A.; Goin-Kochel, Robin P.; Simpson, Gayle; Immken, LaDonna; Haque, Muhammad E.; Stosic, Marija; Williams, Misti; Morgan, Thomas M.; Pruthi, Sumit; Omary, Reed A.; Boyadjiev, Simeon A.; Win, Kay K.; Thida, Aye; Hurles, Matthew; Hibberd, Martin L.; Khor, Chiea Chuen; Châu, Nguyễn Văn Vĩnh; Gallagher, Thomas E.; Mutirangura, Apiwat; Stankiewicz, Paweł; Beaudet, Arthur L.; Maletić-Savatić, Mirjana; Rosenfeld, Jill A.; Shaffer, Lisa G.; Davis, Erica E.; Belmont, John W.; Dunstan, Sarah J.; Simmons, Cameron P.; Bonnen, Penelope E.; Leal, Suzanne M.; Katsanis, Nicholas; Lupski, James R.; Lalani, Seema R.

doi:10.1016/j.ajhg.2013.07.001

Cited by 17 publications

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“…A rare deletion affecting TM4SF20 found in Southeast Asian populations is associated with language delay and white matter abnormalities (198). Structural variation affecting CTNND2, a gene implicated in synapse formation, has been observed in cases of dyslexia with mild ID, as well as in children with severe autism (8,67,178).…”

Section: Structural Variation In Language-related Disordersmentioning

confidence: 99%

Understanding Language from a Genomic Perspective

2015

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Language is a defining characteristic of the human species, but its foundations remain mysterious. Heritable disorders offer a gateway into biological underpinnings, as illustrated by the discovery that FOXP2 disruptions cause a rare form of speech and language impairment. The genetic architecture underlying language-related disorders is complex, and although some progress has been made, it has proved challenging to pinpoint additional relevant genes with confidence. Next-generation sequencing and genome-wide association studies are revolutionizing understanding of the genetic bases of other neurodevelopmental disorders, like autism and schizophrenia, and providing fundamental insights into the molecular networks crucial for typical brain development. We discuss how a similar genomic perspective, brought to the investigation of language-related phenotypes, promises to yield equally informative discoveries. Moreover, we outline how follow-up studies of genetic findings using cellular systems and animal models can help to elucidate the biological mechanisms involved in the development of brain circuits supporting language.

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Section: Structural Variation In Language-related Disordersmentioning

confidence: 99%

Understanding Language from a Genomic Perspective

2015

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“…Interestingly, the same exon 3 deletion has also been detected in samples from several individuals in our patient population, and deletions in IL7R have been reported in the Database of Genomic Variants (http://dgv.tcag.ca) [51]. Thus, a recessive CNV carrier state for this gene may be present in subsets of the general population [52].…”

Section: Discussionmentioning

confidence: 83%

Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL 7 R detected by tandem whole exome sequencing and chromosomal microarray

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Martinez

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et al. 2014

Clinical and Experimental Immunology

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SummaryIn areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8 + T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to highrisk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.

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“…Non-European populations carry a number of unique genetic variants not found in Europeans, some of which might contribute to risk of language-related problems. A recent example is the report of a deletion in TM4SF20 in southeast Asian populations implicated in language delay and cerebral white matter hyperintensities, probably via production of a toxic protein (OMIM 615432) (Wiszniewski et al 2013). Second, languages are diverse in their phonology and syntax (Evans and Levinson 2009), and also in their orthographic systems, which leads to different manifestations of disorders such as SLI and dyslexia (Leonard 2014;Richlan 2014).…”

Section: Social (Pragmatic) Communication Disordermentioning

confidence: 99%

Insights into the Genetic Foundations of Human Communication

2015

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The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

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TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities

Cited by 17 publications

References 0 publications

Understanding Language from a Genomic Perspective

Understanding Language from a Genomic Perspective

Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL 7 R detected by tandem whole exome sequencing and chromosomal microarray

Insights into the Genetic Foundations of Human Communication

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