Human Gene 41 (2024) 201323 Available online 2 August 2024 2773-0441/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Pitt Hopkins syndrome – TCF4 gene deletion causing severe psychomotor delay A.R. Ajina Khan 1 , Betsy Baby 1 , S.L. Akhil , Soumya Sundaram , Karthika Ajit Valaparambil * Pediatric Neurology and Neurodevelopmental Disorders, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India ARTICLE INFO Keywords: Pitt-Hopkins syndrome TCF4 gene Chromosomal microarray analysis (CMA) Autism spectrum disorder ABSTRACT Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder due to haploinsufficiency of TCF4 and is clinically characterized by developmental delay, intellectual disability (ID), autism spectrum disorders, typical facial gestalt, seizures, high myopia and hyperventilation-apneic spells. Approximately in three-fourth cases of PTHS, a de novo pathogenic variant in TCF4 is identified. In other instances, deletion of the chromosome region 18q21.2 in which encompasses TCF4 is responsible and only chromosomal microarray (CMA) can reveal the micro- deletion. This report describes the case of a 10 year-old girl with PTHS phenotype caused by a chromosome 18q21.2q22.1 deletion that included the TCF4 gene. The patient had severe developmental and cognitive delay, autistic spectrum disorder, motor difficulties, and behavioral issues, all of which are typical with PTHS. Un- derstanding the phenotypic variation is critical for accurate diagnosis in this syndrome, since deletions in TCF4 may be missed if exome sequencing is sought instead of chromosomal microarray analysis (CMA). 1. Introduction Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder due to haploinsufficiency of TCF4 and is clinically characterized by develop- mental delay, intellectual disability (ID), autism spectrum disorders, typical facial gestalt, seizures, high myopia and hyperventilation-apneic spells (Van Balkom et al., 2012). Other well recognized syndromes including Angelman and Rett syndrome share a similar phenotype but the distinct facial features such as the prominence of the nose, broad nasal ridge, enlarged nostrils, overhanging nasal tip and lower face, deeply set eyes with prominent supraorbital ridges, short philtrum, wide mouth with downturned corners and widely spaced teeth along with severity of intellectual disability, and behavioral issues distinguishes this disorder from others (Dean, 2012; Teixeira et al., 2021). Approxi- mately in three-fourth cases of PTHS, a de novo pathogenic variant in TCF4 is identified. In other instances, deletion of the chromosome region 18q21.2 in which TCF4 is located is responsible and only chromosomal microarray (CMA) can reveal the microdeletion (Dean, 2012). TCF4 is a basic helix loop helix protein E protein involved in diverse biological process such as B- and T-cell development, initial stages of brain development and neuronal differentiation (Zhuang et al., 1996). The genetic spectrum of TCF4 mutations causing PTHS includes single nucleotide variants and also large deletions of the gene partially or entirely (Teixeira et al., 2021). The most frequently encountered vari- ants are the truncating variants including frame shift, nonsense, splice site variants and large deletions of 18q21 (Zollino et al., 2019). Phenotypic alterations have been observed depending on the molecular diagnosis despite the initial assumption of PTHS phenotype being similar regardless of the genotype (Hasi et al., 2011; Mary et al., 2018; Whalen et al., 2012). Among the missense variants, variable degrees of developmental delay and intellectual disability have been observed. It was postulated that the mutations that caused mild conformational changes resulted in a less severe phenotype compared to the ones that affected DNA binding directly or indirectly (Zhao et al., 2021). In addition, missense mutations in TCF4 have been associated with epi- lepsy (Rosenfeld et al., 2009). In depth genotype phenotype correlation has not yet been systematically delineated. Diagnosis may require either exome sequencing or CMA for detecting the denovo variant or deletion respectively. The genetic diagnosis can be missed if the genetic testing fails to elucidate the underlying molecular mechanism. Here, we present the case of a 10 year old girl with chro- mosome 18q21.2 deletion causing severe phenotype of PTHS. * Corresponding author at: Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, Kerala, India. E-mail address: karthikaajitv@gmail.com (K.A. Valaparambil). 1 These two authors contributed equally as first authors Contents lists available at ScienceDirect Human Gene journal homepage: www.journals.elsevier.com/human-gene https://doi.org/10.1016/j.humgen.2024.201323 Received 6 June 2024; Received in revised form 18 July 2024; Accepted 31 July 2024