Vetrini, FrancescoMcKee, ShaneRosenfeld, Jill A.Suri, MohnishLewis, Andrea M.Nugent, Kimberly MargaretRoeder, ElizabethLittlejohn, Rebecca O.Holder, SueZhu, WenmiaoAlaimo, Joseph T.Graham, BrettHarris, Jill M.Gibson, James B.Pastore, MatthewMcBride, Kim L.Komara, MakankoAl-Gazali, LihadhAl Shamsi, AishaFanning, Elizabeth A.Wierenga, Klaas J.Scott, Daryl A.Ben-Neriah, ZivaMeiner, VardiellaCassuto, HanochElpeleg, OrlyHolder, J. Lloyd, Jr.Burrage, Lindsay C.Seaver, Laurie H.Van Maldergem, LionelMahida, SonalSoul, Janet S.Marlatt, MargaretMatyakhina, LudmilaVogt, JulieGold, June-AnnePark, Soo-MiVarghese, VinodLampe, Anne K.Kumar, AjithLees, MelissaHolder-Espinasse, MurielMcConnell, VivienneBernhard, BirgittaBlair, EdHarrison, VictoriaThe DDD studyMuzny, Donna M.Gibbs, Richard A.Elsea, Sarah H.Posey, Jennifer E.Bi, WeiminLalani, SeemaXia, FanYang, YapingEng, Christine M.Lupski, James R.Liu, Pengfei2019-09-032019-09-032019-02-28Vetrini, F., McKee, S., Rosenfeld, J. A., Suri, M., Lewis, A. M., Nugent, K. M., … 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, 11(1), 12. doi:10.1186/s13073-019-0623-0https://hdl.handle.net/1805/20759BACKGROUND: 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.en-USAttribution 3.0 United States22q13DeletionsHaploinsufficiencyLoss-of-function variantsNeurodevelopmental disordersSmith–Magenis syndromeTCF20Article