De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome
Autor: | Yaping Yang, Sarah H. Elsea, Orly Elpeleg, Donna M. Muzny, Vinod Varghese, Hanoch Cassuto, Mohnish Suri, Sue Holder, AK Lampe, Weimin Bi, Wenmiao Zhu, Muriel Holder-Espinasse, Shane McKee, Christine M. Eng, Lihadh Al-Gazali, Vardiella Meiner, Aisha Al Shamsi, Kim L. McBride, Melissa Lees, June Anne Gold, Janet S. Soul, Soo Mi Park, Birgitta Bernhard, Sonal Mahida, Klaas J. Wierenga, Daryl A. Scott, Elizabeth Roeder, Kimberly Nugent, Vivienne McConnell, Jill M. Harris, Ed Blair, J. Lloyd Holder, Makanko Komara, Seema R. Lalani, Brett H. Graham, Andrea M. Lewis, Jill A. Rosenfeld, Ziva Ben-Neriah, Elizabeth A. Fanning, Richard A. Gibbs, Pengfei Liu, Lionel Van Maldergem, Fan Xia, Ludmila Matyakhina, James B. Gibson, Victoria Harrison, Julie Vogt, Francesco Vetrini, Rebecca O. Littlejohn, James R. Lupski, Ajith Kumar, Jennifer E. Posey, Margaret Marlatt, Joseph T. Alaimo, Matthew Pastore, Laurie H. Seaver, Lindsay C. Burrage |
---|---|
Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine lcsh:QH426-470 Adolescent Developmental Disabilities lcsh:Medicine Haploinsufficiency Craniofacial Abnormalities Young Adult 03 medical and health sciences 0302 clinical medicine INDEL Mutation Intellectual Disability Intellectual disability Genetics medicine Humans Deletions Child Molecular Biology Typographical error Genetics (clinical) TCF20 Loss-of-function variants Research lcsh:R Neurodevelopmental disorders Infant Smith–Magenis syndrome medicine.disease Research Highlight 22q13 Hypotonia 3. Good health lcsh:Genetics 030104 developmental biology Child Preschool 030220 oncology & carcinogenesis Muscle Hypotonia Molecular Medicine Female Smith-Magenis Syndrome medicine.symptom Psychology Transcription Factors Clinical psychology |
Zdroj: | Genome Medicine Genome Medicine, Vol 11, Iss 1, Pp 1-17 (2019) |
ISSN: | 1756-994X |
Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
Externí odkaz: |