Mutations in TCF4, Encoding a Class I Basic Helix-Loop-Helix Transcription Factor, Are Responsible for Pitt-Hopkins Syndrome, a Severe Epileptic Encephalopathy Associated with Autonomic Dysfunction

• Published in: American journal of human genetics Vol. 80; no. 5; pp. 988 - 993
• Main Authors: Amiel, Jeanne, Rio, Marlène, Pontual, Loïc de, Redon, Richard, Malan, Valérie, Boddaert, Nathalie, Plouin, Perrine, Carter, Nigel P., Lyonnet, Stanislas, Munnich, Arnold, Colleaux, Laurence
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.05.2007; University of Chicago Press; Cell Press; Elsevier (Cell Press); The American Society of Human Genetics
• Subjects: Amino Acid Sequence; Autonomic Nervous System Diseases - complications; Autonomic Nervous System Diseases - genetics; Autonomic Nervous System Diseases - pathology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biological and medical sciences; Brain diseases; Child; Child, Preschool; Chromosome Deletion; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 18 - genetics; DNA-Binding Proteins; Epilepsy - complications; Epilepsy - genetics; Epilepsy - pathology; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Helix-Loop-Helix Motifs - genetics; Human genetics; Humans; Life Sciences; Magnetic Resonance Imaging; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Nervous system (semeiology, syndromes); Neurology; Phenotype; Proteins; Sequence Homology, Amino Acid; Syndrome; TCF Transcription Factors - genetics; Transcription Factor 4; Transcription Factor 7-Like 2 Protein; Transcription Factors; Human; Nervous system diseases; Epilepsy; Syndrome; Cerebral disorder; Pinna; Association; Dysfunction; Encephalopathy; Central nervous system disease; Genetics; Mutation; Transcription factor; Severe
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/515582

Pitt-Hopkins syndrome (PHS) is a rare syndromic encephalopathy characterized by daily bouts of hyperventilation and a facial gestalt. We report a 1.8-Mb de novo microdeletion on chromosome 18q21.1, identified by array–comparative genomic hybridization in one patient with PHS. We subsequently identified two de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene in three additional subjects with PHS. These findings demonstrate that TCF4 anomalies are responsible for PHS and provide the first evidence of a human disorder related to class I basic helix-loop-helix transcription-factor defects (also known as “E proteins”). Moreover, our data may shed new light on the normal processes underlying autonomic nervous system development and maintenance of an appropriate ventilatory neuronal circuitry.