Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Abstract

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.

Diagnosis and management in Pitt‐Hopkins syndrome: First international consensus statement

“…Several TCF4 variants associated with non‐specific mild intellectual disability have been described, as well as variants associated with more severe intellectual disability and a limited number of PTHS characteristics. These variants probably include gene disruptive/truncating mutations, a non‐frameshift insertion of an amino acid, translocations, and partial gene deletions . Some of these variants segregated in families together with mild intellectual disability .…”

“…Some of these variants segregated in families together with mild intellectual disability . A recent study reevaluated the clinical phenotype of 10 patients with non‐specific ID without clinical suspicion of PTHS, in whom a TCF4 variant was identified by high‐throughput sequencing . In retrospect, five had typical PTHS, three were clinically classified as possible PTHS and two did not resemble PTHS.…”

“…This may explain the phenotypic differences and the milder signs and symptoms associated with N‐terminal variants . The nature of variants may also explain the phenotype, as a variant in the splice acceptor of exon 17, predicted to result in an in‐frame inclusion of one amino acid, or a splice variant in splice donor of exon 12, which might be leaky, were associated with non‐specific mild or moderate intellectual disability …”

“…These variants probably include gene disruptive/truncating mutations, a non-frameshift insertion of an amino acid, translocations, and partial gene deletions. 22,26,29,[33][34][35][36][37] Some of these variants segregated in families together with mild intellectual disability. 29…”

Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

“…In humans, the TCF4 gene consists of 20 exons, 18 of which are protein-coding. Heterozygote loss-of-function mutations of TCF4 before exon 7 have been linked to nonspeci c intellectual disability (2)(3)(4), while heterozygote disrupting mutations after exon 9 have been causally linked to Pitt-Hopkins Syndrome (PTHS, MIM #610954), a neurodevelopmental disorder characterized by distinctive facial features, moderate to severe intellectual disability, autistic behavior, intermittent breathing abnormalities, seizures (5)(6)(7). Moreover, SNPs in non-coding regions of the TCF4 gene are associated with an increased risk of schizophrenia and autism (8)(9)(10)(11).…”