De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome

Francesco Vetrini, Shane McKee, Jill A. Rosenfeld, Mohnish Suri, Andrea M. Lewis, Kimberly Margaret Nugent, Elizabeth Roeder, Rebecca O. Littlejohn, Sue Holder, Wenmiao Zhu, Joseph T. Alaimo, Brett Graham, Jill M. Harris, James B. Gibson, Matthew Pastore, Kim L. McBride, Makanko Komara, Lihadh Al-Gazali, Aisha Al Shamsi, Elizabeth A. FanningKlaas J. Wierenga, Daryl A. Scott, Ziva Ben-Neriah, Vardiella Meiner, Hanoch Cassuto, Orly Elpeleg, J. Lloyd Holder, Lindsay C. Burrage, Laurie H. Seaver, Lionel Van Maldergem, Sonal Mahida, Janet S. Soul, Margaret Marlatt, Ludmila Matyakhina, Julie Vogt, June Anne Gold, Soo Mi Park, Vinod Varghese, Anne K. Lampe, Ajith Kumar, Melissa Lees, Muriel Holder-Espinasse, Vivienne McConnell, Birgitta Bernhard, Ed Blair, Victoria Harrison, Donna M. Muzny, Richard A. Gibbs, Sarah H. Elsea, Jennifer E. Posey, Weimin Bi, Seema Lalani, Fan Xia, Yaping Yang, Christine M. Eng, James R. Lupski, Pengfei Liu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

Original languageEnglish (US)
Article number12
JournalGenome Medicine
Volume11
Issue number1
DOIs
StatePublished - Feb 28 2019

Fingerprint

Smith-Magenis Syndrome
Muscle Hypotonia
Intellectual Disability
Parents
Alleles
Exome
Phenotype
Haploinsufficiency
Gene Dosage
Monozygotic Twins
Movement Disorders
Microarray Analysis
Neurologic Manifestations
Sleep
Nucleotides
Genotype
Genome
Mutation
Brain
Genes

Keywords

  • 22q13
  • Deletions
  • Haploinsufficiency
  • Loss-of-function variants
  • Neurodevelopmental disorders
  • Smith-Magenis syndrome
  • TCF20

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. / Vetrini, Francesco; McKee, Shane; Rosenfeld, Jill A.; Suri, Mohnish; Lewis, Andrea M.; Nugent, Kimberly Margaret; Roeder, Elizabeth; Littlejohn, Rebecca O.; Holder, Sue; Zhu, Wenmiao; Alaimo, Joseph T.; Graham, Brett; Harris, Jill M.; Gibson, James B.; Pastore, Matthew; McBride, Kim L.; Komara, Makanko; Al-Gazali, Lihadh; Al Shamsi, Aisha; Fanning, Elizabeth A.; Wierenga, Klaas J.; Scott, Daryl A.; Ben-Neriah, Ziva; Meiner, Vardiella; Cassuto, Hanoch; Elpeleg, Orly; Holder, J. Lloyd; Burrage, Lindsay C.; Seaver, Laurie H.; Van Maldergem, Lionel; Mahida, Sonal; Soul, Janet S.; Marlatt, Margaret; Matyakhina, Ludmila; Vogt, Julie; Gold, June Anne; Park, Soo Mi; Varghese, Vinod; Lampe, Anne K.; Kumar, Ajith; Lees, Melissa; Holder-Espinasse, Muriel; McConnell, Vivienne; Bernhard, Birgitta; Blair, Ed; Harrison, Victoria; Muzny, Donna M.; Gibbs, Richard A.; Elsea, Sarah H.; Posey, Jennifer E.; Bi, Weimin; Lalani, Seema; Xia, Fan; Yang, Yaping; Eng, Christine M.; Lupski, James R.; Liu, Pengfei.

In: Genome Medicine, Vol. 11, No. 1, 12, 28.02.2019.

Research output: Contribution to journalArticle

Vetrini, F, McKee, S, Rosenfeld, JA, Suri, M, Lewis, AM, Nugent, KM, Roeder, E, Littlejohn, RO, Holder, S, Zhu, W, Alaimo, JT, Graham, B, Harris, JM, Gibson, JB, Pastore, M, McBride, KL, Komara, M, Al-Gazali, L, Al Shamsi, A, Fanning, EA, Wierenga, KJ, Scott, DA, Ben-Neriah, Z, Meiner, V, Cassuto, H, Elpeleg, O, Holder, JL, Burrage, LC, Seaver, LH, Van Maldergem, L, Mahida, S, Soul, JS, Marlatt, M, Matyakhina, L, Vogt, J, Gold, JA, Park, SM, Varghese, V, Lampe, AK, Kumar, A, Lees, M, Holder-Espinasse, M, McConnell, V, Bernhard, B, Blair, E, Harrison, V, Muzny, DM, Gibbs, RA, Elsea, SH, Posey, JE, Bi, W, Lalani, S, Xia, F, Yang, Y, Eng, CM, Lupski, JR & Liu, P 2019, 'De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome', Genome Medicine, vol. 11, no. 1, 12. https://doi.org/10.1186/s13073-019-0623-0
Vetrini, Francesco ; McKee, Shane ; Rosenfeld, Jill A. ; Suri, Mohnish ; Lewis, Andrea M. ; Nugent, Kimberly Margaret ; Roeder, Elizabeth ; Littlejohn, Rebecca O. ; Holder, Sue ; Zhu, Wenmiao ; Alaimo, Joseph T. ; Graham, Brett ; Harris, Jill M. ; Gibson, James B. ; Pastore, Matthew ; McBride, Kim L. ; Komara, Makanko ; Al-Gazali, Lihadh ; Al Shamsi, Aisha ; Fanning, Elizabeth A. ; Wierenga, Klaas J. ; Scott, Daryl A. ; Ben-Neriah, Ziva ; Meiner, Vardiella ; Cassuto, Hanoch ; Elpeleg, Orly ; Holder, J. Lloyd ; Burrage, Lindsay C. ; Seaver, Laurie H. ; Van Maldergem, Lionel ; Mahida, Sonal ; Soul, Janet S. ; Marlatt, Margaret ; Matyakhina, Ludmila ; Vogt, Julie ; Gold, June Anne ; Park, Soo Mi ; Varghese, Vinod ; Lampe, Anne K. ; Kumar, Ajith ; Lees, Melissa ; Holder-Espinasse, Muriel ; McConnell, Vivienne ; Bernhard, Birgitta ; Blair, Ed ; Harrison, Victoria ; Muzny, Donna M. ; Gibbs, Richard A. ; Elsea, Sarah H. ; Posey, Jennifer E. ; Bi, Weimin ; Lalani, Seema ; Xia, Fan ; Yang, Yaping ; Eng, Christine M. ; Lupski, James R. ; Liu, Pengfei. / De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. In: Genome Medicine. 2019 ; Vol. 11, No. 1.
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title = "De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome",
abstract = "Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.",
keywords = "22q13, Deletions, Haploinsufficiency, Loss-of-function variants, Neurodevelopmental disorders, Smith-Magenis syndrome, TCF20",
author = "Francesco Vetrini and Shane McKee and Rosenfeld, {Jill A.} and Mohnish Suri and Lewis, {Andrea M.} and Nugent, {Kimberly Margaret} and Elizabeth Roeder and Littlejohn, {Rebecca O.} and Sue Holder and Wenmiao Zhu and Alaimo, {Joseph T.} and Brett Graham and Harris, {Jill M.} and Gibson, {James B.} and Matthew Pastore and McBride, {Kim L.} and Makanko Komara and Lihadh Al-Gazali and {Al Shamsi}, Aisha and Fanning, {Elizabeth A.} and Wierenga, {Klaas J.} and Scott, {Daryl A.} and Ziva Ben-Neriah and Vardiella Meiner and Hanoch Cassuto and Orly Elpeleg and Holder, {J. Lloyd} and Burrage, {Lindsay C.} and Seaver, {Laurie H.} and {Van Maldergem}, Lionel and Sonal Mahida and Soul, {Janet S.} and Margaret Marlatt and Ludmila Matyakhina and Julie Vogt and Gold, {June Anne} and Park, {Soo Mi} and Vinod Varghese and Lampe, {Anne K.} and Ajith Kumar and Melissa Lees and Muriel Holder-Espinasse and Vivienne McConnell and Birgitta Bernhard and Ed Blair and Victoria Harrison and Muzny, {Donna M.} and Gibbs, {Richard A.} and Elsea, {Sarah H.} and Posey, {Jennifer E.} and Weimin Bi and Seema Lalani and Fan Xia and Yaping Yang and Eng, {Christine M.} and Lupski, {James R.} and Pengfei Liu",
year = "2019",
month = "2",
day = "28",
doi = "10.1186/s13073-019-0623-0",
language = "English (US)",
volume = "11",
journal = "Genome Medicine",
issn = "1756-994X",
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TY - JOUR

T1 - De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome

AU - Vetrini, Francesco

AU - McKee, Shane

AU - Rosenfeld, Jill A.

AU - Suri, Mohnish

AU - Lewis, Andrea M.

AU - Nugent, Kimberly Margaret

AU - Roeder, Elizabeth

AU - Littlejohn, Rebecca O.

AU - Holder, Sue

AU - Zhu, Wenmiao

AU - Alaimo, Joseph T.

AU - Graham, Brett

AU - Harris, Jill M.

AU - Gibson, James B.

AU - Pastore, Matthew

AU - McBride, Kim L.

AU - Komara, Makanko

AU - Al-Gazali, Lihadh

AU - Al Shamsi, Aisha

AU - Fanning, Elizabeth A.

AU - Wierenga, Klaas J.

AU - Scott, Daryl A.

AU - Ben-Neriah, Ziva

AU - Meiner, Vardiella

AU - Cassuto, Hanoch

AU - Elpeleg, Orly

AU - Holder, J. Lloyd

AU - Burrage, Lindsay C.

AU - Seaver, Laurie H.

AU - Van Maldergem, Lionel

AU - Mahida, Sonal

AU - Soul, Janet S.

AU - Marlatt, Margaret

AU - Matyakhina, Ludmila

AU - Vogt, Julie

AU - Gold, June Anne

AU - Park, Soo Mi

AU - Varghese, Vinod

AU - Lampe, Anne K.

AU - Kumar, Ajith

AU - Lees, Melissa

AU - Holder-Espinasse, Muriel

AU - McConnell, Vivienne

AU - Bernhard, Birgitta

AU - Blair, Ed

AU - Harrison, Victoria

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Elsea, Sarah H.

AU - Posey, Jennifer E.

AU - Bi, Weimin

AU - Lalani, Seema

AU - Xia, Fan

AU - Yang, Yaping

AU - Eng, Christine M.

AU - Lupski, James R.

AU - Liu, Pengfei

PY - 2019/2/28

Y1 - 2019/2/28

N2 - Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

AB - Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

KW - 22q13

KW - Deletions

KW - Haploinsufficiency

KW - Loss-of-function variants

KW - Neurodevelopmental disorders

KW - Smith-Magenis syndrome

KW - TCF20

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DO - 10.1186/s13073-019-0623-0

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