Pitt–Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations

Zhao, Tingting; Genchev, Georgi Z.; Wu, Shengnan; Yu, Guangjun; Lü, Hui; Feng, Jincai

doi:10.1007/s10048-021-00651-8

Cited by 6 publications

(11 citation statements)

References 42 publications

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“…Moreover, Zhao et al reported three other patients with exon 18 missense variants that were positioned very close to the variant we report; all three patients had severe phenotypes, including absent or limited speech and severe intellectual disability (Zhao et al, 2021).…”

Section: Discussionsupporting

confidence: 68%

“…For instance, a nearby missense variant (c.1841C > T p.Ala614Val), that is only three amino acids upstream from our patients' variant, was reported in a 7‐year‐old female with severe intellectual disability, absent speech, severe motor delay (walked at age 5), ataxia, and abnormal cerebral MRI (patient B00H4R8, Mary et al, 2018). Moreover, Zhao et al reported three other patients with exon 18 missense variants that were positioned very close to the variant we report; all three patients had severe phenotypes, including absent or limited speech and severe intellectual disability (Zhao et al, 2021).…”

Section: Discussionsupporting

confidence: 61%

“…Although the three affected individuals shared some facial features of PTHS, those were rather mild and not specific enough to hint at PTHS. Similarly, Zhao et al (2021) reported the same variant in a mildly affected 2.5‐year‐old Chinese girl. The girl in Zhao et al walked at the age of 21 months, had occasional two‐word sentences, and could count to 10 (Zhao et al, 2021).…”

Section: Discussionmentioning

confidence: 70%

“…Similarly, Zhao et al (2021) reported the same variant in a mildly affected 2.5‐year‐old Chinese girl. The girl in Zhao et al walked at the age of 21 months, had occasional two‐word sentences, and could count to 10 (Zhao et al, 2021). Table 1 compares the patient reported by Zhao et al and our three affected individuals with the same c.1849G > A (p.Val617Ile) TCF4 variant, using the clinical diagnostic criteria provided by Zollino et al (2019).…”

Section: Discussionmentioning

confidence: 70%

“…While the variability between all TCF4 ‐related disorders can be quite challenging to explain, Figure 3 demonstrates the tendency of the variants associated with typical PTHS to cluster at the protein–DNA interface. For instance, Zhao et al (2021) reported three individuals with severe PTHS phenotype and missense variants impacting amino acids positioned close to the DNA strand. This is to be contrasted with the p.Val617Ile variant that is spatially far from the protein–DNA interface.…”

Section: Discussionmentioning

confidence: 99%

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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

Aldeeri

Abu‐El‐Haija

2022

American J of Med Genetics Pt A

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TCF4 gene encodes a class I helix–loop–helix transcription factor critical for the developing brain. Common polymorphisms in TCF4 and disruptive variants in the proximal region of the gene have been linked to relatively mild neuropsychiatric or neurodevelopmental disorders. In contrast, variants impacting distal exons are associated with Pitt–Hopkins syndrome (PTHS), a severe autosomal dominant condition characterized by profound intellectual disability, developmental delay, limited or absent speech, distinctive facies, and disordered breathing. Although phenotypic variability has been observed in PTHS, intellectual impairment and significant speech and motor delays are invariably present. In contrast to the typical de novo variants causing TCF4‐related disorder and PTHS, we report a familial form of TCF4‐related disorder where the missense variant arose de novo in the father and was inherited by two of his children. Although this family's variant's position in exon 18 predicted a typical PTHS phenotype, none of the affected individuals met the clinical diagnostic criteria for PTHS suggested by Zollino et al. in the first international consensus statement (as in the study by Zollino et al. in 2019). Rather, the three affected family members exhibited remarkably variable and milder phenotypes than would have been predicted from the position of their TCF4 variant. Thus, the clinical spectrum of PTHS‐associated TCF4 variants may be broader than previously reported.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 61%