|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.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Vetrini, F, McKee, S, Rosenfeld, JA, Suri, M, Lewis, AM, Nugent, KMargaret, 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, Shamsi, AAl, Fanning, EA, Wierenga, KJ, Scott, DA, Ben-Neriah, Z, Meiner, V, Cassuto, H, Elpeleg, O, J Holder, L, Burrage, LC, Seaver, LH, Van Maldergem, L, Mahida, S, Soul, JS, Marlatt, M, Matyakhina, L, Vogt, J, Gold, J-A, Park, S-M, 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|
|Corporate Authors||DDD study|
|Date Published||2019 Feb 28|
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.
|Alternate Journal||Genome Med|
|Grant List||K08 HG008986 / / National Human Genome Research Institute / |
UM1HG006542 / / NHGRI/NHLBI /
R35 NS105078-01 / / National Institute of Neurological Disorders and Stroke /
HICF-1009-003 / / Health Innovation Challenge Fund /
WT098051 / / Wellcome Trust (GB) /