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. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

Disentangling the determinants of transposable elements dynamics in vertebrate genomes using empirical evidences and simulations

“…We found in total four elements that are serious candidate for positive selection, falling in introns of Neurexin2 and TCF1-220 . Neurexin2 is involved in the neurotransmitter release [53], while TCF20-201 is a transcription factor associated with behavioral abnormalities [54, 55]. While this suggests a potential impact on the nervous system and behavior, and echoes our findings from a previous study on positive selection in green anoles [52], further investigations are needed to formally validate the causal role of these elements and discard the possibility that they are only linked to a causal variant under selection.…”

Disentangling the determinants of transposable elements dynamics in vertebrate genomes using empirical evidences and simulations

“…PTBP3 is involved in cell growth and erythropoiesis [ 63 ]. Neurexins are involved in the neurotransmitter release [ 64 ], while TCF20-201 is a transcription factor associated with behavioral abnormalities [ 65 , 66 ]. While this suggests a potential impact on the nervous system and behavior, and echoes our findings from a previous study on positive selection in green anoles [ 62 ], further investigations are needed to formally validate the causal role of these elements and discard the possibility that they are only linked to a causal variant under selection.…”

Molecular basis for phenotypic similarity of genetic disorders

“…Several of these studies have unraveled specific genes that are associated with rare Mendelian disorders, whereas others have identified numerous genes that contribute to similar disorders with shared phenotypes. In a recent study, Liu and colleagues analyzed exome sequencing and chromosomal microarray data and identified pathogenic mutations in TCF20 in 32 affected individuals from 31 unrelated families [5]. TCF20 encodes an SPRE-binding transcription factor that is strongly expressed in pre-migratory neural crest cells and is known to influence other transcription factors [6].…”

“…Liu and colleagues found that commonalities in gene structure and function between TCF20 and RAI1 could explain the shared core clinical features and molecular effects [5]. In fact, TCF20 shares several essential protein domains with RAI1 , including N-terminal transactivation domains, zinc-finger-like plant homeodomains (PHD), and nuclear localization signal domains [6].…”

“…In fact, TCF20 shares several essential protein domains with RAI1 , including N-terminal transactivation domains, zinc-finger-like plant homeodomains (PHD), and nuclear localization signal domains [6]. The high sequence homology and conservation of specific domain combinations between TCF20 and RAI1 is attributed to a gene duplication event that occurred during early vertebrate evolution [5]. For example, the chromatin-binding PHD domain is highly conserved in both TCF20 and RAI1 , and a patient with a missense mutation in the PHD domain of TCF20 presented with strong SMS-like features [5].…”