The recurrent TCF4 missense variant p.(Arg389Cys) causes a neurodevelopmental disorder overlapping with but not typical for Pitt‐Hopkins syndrome

Abstract

TCF4 haploinsufficiency by deletions, truncating variants or loss‐of‐function missense variants within the DNA‐binding and protein interacting bHLH domain causes Pitt‐Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N‐terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non‐specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator‐recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype–phenotype correlation for TCF4‐related NDDs.

A typical variant in TCF4 exon 18 is not associated with Pitt–Hopkins syndrome but with a familial case of mild and nonspecific neurodevelopmental disorder

“…(Arg389Cys) in exon 15; all with moderate to severe intellectual disability and other features; however, not fulfilling the diagnostic criteria for PTHS (Popp et al, 2022). The underlying mechanism of the phenotypic variability of TCF4-related disorders remains complex and not fully understood at this time.…”

“…On the other hand, variants affecting the proximal part of the TCF4 gene have been found to produce a milder phenotype of intellectual disability and other nonspecific features (Masson et al, 2022). For instance, Popp et al recently reported a series of six individuals with the de novo variant c.1165C > T, p.(Arg389Cys) in exon 15; all with moderate to severe intellectual disability and other features; however, not fulfilling the diagnostic criteria for PTHS (Popp et al, 2022). The underlying mechanism of the phenotypic variability of TCF4 ‐related disorders remains complex and not fully understood at this time.…”

A patient with Pitt–Hopkins syndrome with concomitant common variable immunodeficiency

“…Less is known about immunologic function, specifically in Pitt–Hopkins syndrome (PTHS), a condition due to either copy number variants at 18q or other variants impacting one T‐cell factor 4 ( TCF4 ) allele. A recurrent missense variant in TCF4 causes a milder phenotype (Popp et al, 2022), and overall, there is variability related to the variant effect (haplosufficiency, dominant negative, and hypomorphic), and 5′ variants can be associated with non‐syndromic developmental delay (Bedeschi et al, 2017). PTHS is thought to have a population frequency of 1:34,000 to 1:41,000 based on chromosomal microarray data (Goodspeed et al, 2018; Zollino et al, 2019).…”

Expanding the phenotype in Pitt-Hopkins syndrome; description of new oral finding and dental management considerations

“…TCF4 is a protein-coding gene that is located at the long arm of chromosome 18. It encodes the transcription factor 4 (TCF-4) which is expressed in the embryonic central nervous system and plays important roles in neural differentiation and development [5][6][7].…”

“…[6][7][8] Presence of facial characteristics + additional criteria, either cardinal or supportive, totaling a Score of 6-8. This score warrants TCF4 molecular analysis.…”