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.

Fig. 1

TCF20 gene, protein domain structure, and location of mutations. a Schematic representation of TCF20, exons are shown to scale with the coding sequence in gray and untranslated regions in dark blue. There is an in frame stop codon in the alternatively spliced exon 5 generating a shorter isoform (referred as isoform 2) (Genbank: NM_181492.2) lacking exon 5 in the 3′ coding region. The position of the first coding nucleotide is shown in exon 2, numbers above boxes indicate cDNA numbering at last nucleotides of exon boundaries or last nucleotide of stop codons. Red dashed lines show the exon boundaries relative to the amino acid position shown in b. b Domain structures of TCF20 with the mutations currently identified. Protein domains are indicated above or below the structure. Abbreviations as follows: TAD, transactivation domain; NLS, nuclear localization signals; LZ, leucine zipper; DBD, DNA-binding domain; AT-h, AT-hook domain; PHD/ADD, Plant Homeodomain/ADD. In red and below the protein structure are the mutations identified in this study. In black and above the protein structure are the mutations previously reported (see text). All the de novo SNVs detected in anonymized subjects presenting with mild to severe neurodevelopmental disorder from our cohort are represented in green and located below the protein structure. All the mutations occur before the last exon of TCF20. In parentheses are indicated the number of times the recurring variants are observed. c ClustalW multi-species alignment obtained with Alamut software of the region containing Lys1710Arg showing the high level of conservation of the mutated residue. Intensities of shades of blue are proportional to the degree of cross-species conservation

Fig. 2

Twelve individuals with TCF20-associated neurodevelopmental disorder (TAND). Facial features are variable from normal or mildly dysmorphic: subject #8 (b), subject #25 (h), subject #29 (i), and subject #31 (m) to dysmorphic: macrocephaly in subjects #11 (c) and #30 (picture taken at 22 years old) (l); brachycephaly in subject #19 (f); midface hypoplasia in subject #17 and #32 (e, n); long eyelashes, thick lips, and occipital grove in subject #32 (n); upper lip abnormality including tented or thin upper lip in subjects #1, #11, #13, and #17 (a, c, d, e); coarse facies in subjects #1 and #11 (a, c); long face, full cheeks, deep-set eyes, and prominent lower lip in subject #22 (g). Digital anomalies include contracture of the fifth finger in subject #19 (f) and slender fingers in subject #22 (g)

Fig. 3

Schematic representation of 22q13.2 CNVs involving TCF20 identified in this study and DECIPHER. Deletion intervals in the patients are indicated in red, whereas duplications are indicated in green. The four subjects that are clinically characterized in this study are shown on the top of the figure. Subjects #29, #31, and #32 have larger deletions encompassing multiple flanking genes not currently associated with disease. Subject 30 has a deletion encompassing solely TCF20. Anonymized subjects with CNVs affecting TCF20 that are detected by exon-targeted CMA from the Baylor database are shown in the middle. Cases from DECIPHER with a CNV encompassing TCF20 are shown in the bottom of the figure. Genes with a pLI score > 0.9 that are located within any of the deletions shown in this figure are highlighted by blue vertical segments. ZC3H7B, XRCC6, SREBF2, and TCF20 have pLI scores > 0.99. SCUBE1 and SULT4A1 have pLI scores > 0.95